Novel Ferroportin Inhibitors

ABSTRACT

The invention relates to novel compounds of the general formula (I), 
     
       
         
         
             
             
         
       
     
     with Het-2 being an optionally substituted bicyclic heteroaryl of the formula 
     
       
         
         
             
             
         
       
     
     pharmaceutical compositions comprising them and the use thereof as medicaments, in particular for the use as ferroportin inhibitors, more particularly for the use in the prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, such as particularly iron overload states such as in particular thalassemia and hemochromatosis.

CROSS REFERENCE TO RELATED APPLICATIONS

The present invention is a divisional application of copending U.S.patent application Ser. No. 15/769,148, filed Apr. 18, 2018, whichclaims benefit from International Application No. PCT/EP2016/075306filed Oct. 21, 2016, which claims priority to EP 15191176.5 filed Oct.23, 2015 and EP 15191179.9 filed Oct. 23, 2015, all of which areincorporated herein by reference.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jul. 23, 2019, isnamed GIL-44004-01-SL.txt and is 944 bytes in size.

DESCRIPTION Introduction

The invention relates to novel compounds of the general formula (A-I),pharmaceutical compositions comprising them and the use thereof asmedicaments, in particular for the use as ferroportin inhibitors, moreparticularly for the use in the prophylaxis and/or treatment of diseasescaused by a lack of hepcidin or iron metabolism disorders, such asparticularly iron overload states such as in particular thalassemia andhemochromatosis.

BACKGROUND AND PRIOR ART

Iron is an essential trace element for almost all organisms and isrelevant in particular with respect to growth and the formation ofblood. The balance of the iron metabolism is in this case primarilyregulated on the level of iron recovery from haemoglobin of ageingerythrocytes and the duodenal absorption of dietary iron. The releasediron is taken up via the intestine, in particular via specific transportsystems (DMT-1, ferroportin), transferred into the blood circulation andthereby conveyed to the appropriate tissues and organs (transferrin,transferrin receptors).

In the human body, the element iron is of great importance, inter aliafor oxygen transport, oxygen uptake, cell functions such asmitochondrial electron transport, cognitive functions, etc. andultimately for the entire energy metabolism.

On average, the human body contains 4 to 5 g iron, with it being presentin enzymes, in haemoglobin and myoglobin, as well as depot or reserveiron in the form of ferritin and hemosiderin. Approximately half of thisiron, about 2 g, is present as heme iron, bound in the haemoglobin ofthe erythrocytes. Since these erythrocytes have only a limited lifespan(75-150 days), new ones have to be formed continuously and old onesdegraded (over 2 million erythrocytes are being formed per second). Thishigh regeneration capacity is achieved by macrophages phagocytizing theageing erythrocytes, lysing them and thus recycling the iron thusobtained for the iron metabolism. The majority of the iron required forerythropoiesis, about 25 mg per day, is provided in this way.

The daily iron requirement of a human adult is between 0.5 to 1.5 mg perday, infants and women during pregnancy require 2 to 5 mg of iron perday. The daily iron loss, e.g. by desquamation of skin and epithelialcells, is low. Increased iron loss occurs, for example, during menstrualhemorrhage in women.

Generally, blood loss can significantly reduce the iron level sinceabout 1 mg iron is lost per 2 ml blood. In a healthy human adult, thenormal daily loss of iron of about 1 mg is usually replaced via thedaily food intake thus rebalancing the daily iron requirement to theadequate level.

The iron level is regulated by absorption, with the absorption rate ofthe iron present in food being between 6 and 12%, and up to 25% in thecase of iron deficiency. The absorption rate is regulated by theorganism depending on the iron requirement and the size of the ironstore. In the process, the human organism utilizes both divalent as wellas trivalent iron ions. Usually, iron(III) compounds are dissolved inthe stomach at a sufficiently acid pH value and thus made available forabsorption. The absorption of the iron is carried out in the upper smallintestine by mucosal cells. In the process, trivalent non-heme iron isfirst reduced in the intestinal cell membrane to Fe(II) for absorption,for example by ferric reductase (membrane-bound duodenal cytochrome b),so that it can then be transported into the intestinal cells by means ofthe transport protein DMT1 (divalent metal transporter 1). In contrast,heme iron enters the enterocytes through the cell membrane without anychange. In the enterocytes, iron is either stored in ferritin as depotiron, or released into the blood by the transport protein ferroportin.Hepcidin plays a central role in this process because it is theessential regulating factor of iron absorption. The divalent irontransported into the blood by ferroportin is converted into trivalentiron by oxidases (ceruloplasmin, hephaestin), the trivalent iron thenbeing transported to the relevant places in the organism by transferrin(see for example “Balancing acts: molecular control of mammalian ironmetabolism”. M. W. Hentze, Cell 117, 2004, 285-297.).

Mammalian organisms are unable to actively discharge iron. The ironmetabolism is substantially controlled by hepcidin via the cellularrelease of iron from macrophages, hepatocytes and enterocytes.

Hepcidin is a peptide hormone produced in the liver. The predominantactive form has 25 amino acids (see for example: “Hepcidin, a keyregulator of iron metabolism and mediator of anaemia of inflammation”.T. Ganz, Blood, 102, 2003, 783-8), although two forms which areshortened at the amino end, hepcidin-22 and hepcidin-20, have beenfound. Hepcidin acts on the absorption of iron via the intestine and viathe placenta and on the release of iron from the reticuloendothelialsystem. In the body, hepcidin is synthesized in the liver from what isknown as pro-hepcidin, pro-hepcidin being coded by the gene known as theHAMP gene. The formation of hepcidin is regulated in direct correlationto the organisms iron level, i.e. if the organism is supplied withsufficient iron and oxygen, more hepcidin is formed, if iron and oxygenlevels are low, or in case of increased erythropoiesis less hepcidin isformed. In the small intestinal mucosal cells and in the macrophageshepcidin binds with the transport protein ferroportin, whichconventionally transports the phagocytotically recycled iron from theinterior of the cell into the blood.

The transport protein ferroportin is a transmembrane protein consistingof 571 amino acids which is formed in the liver, spleen, kidneys, heart,intestine and placenta. In particular, ferroportin is localized in thebasolateral membrane of intestinal epithelial cells. Ferroportin boundin this way thus acts to export the iron into the blood. In this case,it is most probable that ferroportin transports iron as Fe²⁺. Ifhepcidin binds to ferroportin, ferroportin is transported into theinterior of the cell, where its breakdown takes place so that therelease of the phagocytotically recycled iron from the cells is thenalmost completely blocked. If the ferroportin is inactivated, forexample by hepcidin, so that it is unable to export the iron which isstored in the mucosal cells, the stored iron is lost with the naturalshedding of cells via the stools. The absorption of iron in theintestine is therefore reduced, when ferroportin is inactivated orinhibited, for example by hepcidin. In addition, ferroportin is markedlylocalized in the reticuloendothelial system (RES), to which themacrophages also belong. Hepcidin plays an important part here when ironmetabolism is impaired by chronic inflammation. In case of inflammationin particular interleukin-6 is increased, triggering an increase inhepcidin levels. As a result, more hepcidin is bound to the ferroportinof the macrophages, thus blocking the release of stored iron, whichultimately leads to anemia of inflammation (ACD or Al).

On the other hand, if the serum iron level decreases, hepcidinproduction in the hepatocytes of the liver is reduced so that lesshepcidin is released and accordingly less ferroportin is inactivated,allowing a larger amount of stored iron to be transported into theserum.

Therefrom it becomes apparent that the hepcidin-ferroportin systemdirectly regulates the iron metabolism and that a disorder of thehepcidin regulation mechanism therefore has a direct effect on ironmetabolism in the organism. In principle the hepcidin-ferroportinregulation mechanism acts via the two following opposite principles:

On the one hand, an increase of hepcidin leads to inactivation offerroportin, thus blocking the release of stored iron from the cellsinto the serum, thus decreasing the serum iron level. In pathologicalcases a decreased serum iron level leads to a reduced hemoglobin level,reduced erythrocyte production and thus to iron deficiency anemia.

On the other hand, a decrease of hepcidin results in an increase ofactive ferroportin, thus allowing an enhanced release of stored iron andan enhanced iron uptake e.g. from the food, thus increasing the serumiron level. In pathological cases an increased iron level leads to ironoverload.

Iron overload states and diseases are characterized by excess ironlevels. Therein, the problems arise from excess serum iron level whichlead to non-transferrin bound iron (NTBI). The NTBI is rapidly taken upunspecifically by the organs, leading to an accumulation of iron intissue and organs. Iron overload causes many diseases and undesiredmedical conditions, including cardiac, liver and endocrine damage.Further, iron accumulation in brain has been observed in patientssuffering from neurodegenerative diseases such as for exampleAlzheimer's disease and Parkinson's disease. As a particular detrimentalaspect of excess free iron the undesired formation of radicals must bementioned. In particular iron(II) ions catalyze the formation (interalia via Fenton reaction) of reactive oxygen species (ROS). These ROScause damage to DNA, lipids, proteins and carbohydrates which hasfar-reaching effects in cells, tissue and organs. The formation of ROSis well known and described in the literature to cause the so-calledoxidative stress.

A well-established hitherto existing method for treating iron overloadis based on the concept to reduce the amount of iron in the serum byincreased removal of the iron from the body. The eldest known and stillroutine treatment method in an otherwise-healthy person consists ofregularly scheduled phlebotomies (bloodletting). When first diagnosed,the phlebotomies are usually scheduled fairly frequent, e.g. once aweek, until iron levels are brought to within normal range, followed byphlebotomies which are then scheduled once a month or every three monthsdepending upon the patient's rate of iron loading.

For patients unable to tolerate routine blood draws, there are chelatingagents available for use. For example, deferoxamine (also known asdesferrioxamine B,N′-{5-[acetyl(hydroxy)amino]pentyl}-N-[5-({4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoyl}amino)pentyl]-N-hydroxysuccinamideor Desferal®), which is a bacterial siderophore, is an established drugused in chelation therapy. Deferoxamine binds iron in the bloodstream asan chelator and enhances its elimination via urine and faeces. Typicaltreatment of chronic iron overload requires subcutaneous injection overa period of 8-12 hours daily. Parenterally injectable compositions ofdesferrioxamine-B salts are described for example in WO 1998/25887.

Two newer drugs, licensed for use in patients receiving regular bloodtransfusions to treat thalassemia, resulting in the development of ironoverload, are deferasirox and deferiprone.

Deferasirox (Exjade®,4-(3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl)benzoic acid), beingdescribed for example in WO 1997/49395 and deferiprone (Ferriprox®,3-hydroxy-1,2-dimethylpyridin-4(1H)-one) are similarly acting as an ironchelating agent, thus being suitable as a drug for iron chelationtherapy.

Further compounds acting as iron chelator for use in the treatment ofiron overload have been described. For example WO 2013/142258 relates toencapsulated particles of diethylenetriaminepentaacetate (DTPA) and azinc salt. WO 2003/041709 relates to 4-hydroxy-2-alkylquniolines such as4-hydroxy-2-nonylqunioline as an iron chelator. WO 1998/09626 relates tochelating agents for treating iron overload states on the basis ofdithiocarbamate-containing compositions.

WO 2015/077655 relates to desferrithiocin derivatives of the formula (A)or (J)

for the use in the treatment of iron overload diseases. According to WO2015/077655 said desferrithiocin derivatives have been found to act asiron chelating agents.

WO 2005/051411 relates to novel antibiotics or antimycotics on the basisof oxachelin and derivatives thereof according to formula

which are described to act as an iron chelator and to be used in thetreatment of iron overload diseases.

The disadvantage in the treatment of iron overload by chelation therapyis the removal of the chelated iron from the body when the iron overloadhas already occurred instead of preventing the occurrence of thedisorder. Further, the established drugs for iron chelation therapy areknown to exhibit a toxic potential.

Modern approaches can be expected to supersede this method increasingly,in particular with increasing knowledge about the underlying mechanismsand development of appropriate treating methods on the basis of suchknowledge. Hepcidin agonists or compounds which have an inhibiting orsupporting effect on the biochemical regulatory pathways in the ironmetabolism are basically known from the prior art.

Iron overload may occur, for example, if hepcidin expression isprevented, for example due to a genetic defect, such as in the knowniron overload disease haemochromatosis. Hemochromatosis is a disease ofiron overload caused by mutations in genes that control hepcidinsynthesis or in the hepcidin gene itself. Low or absent levels ofhepcidin in these patients result in enhanced amounts of activeferroportin, allowing increased absorption of dietary iron, leading tosevere iron overload, which causes cardiac, liver and endocrine damages.Hepcidin mimetic peptides, i.e. peptides which similarly bind andinactivate ferroportin, have been shown to effectively reverse theaccumulation of tissue iron in the hepcidin knockout mouse, a model ofType 2 (juvenile) hemochromatosis. (Ramos et al., Blood 2012).

In the known iron overload disease beta-thalassemia a mutation in thebeta globin gene causes a reduction in hemoglobin production andineffective erythropoiesis, the inability to produce adequate numbers ofred cells because of damage to and death of developing red cells in thebone marrow. This causes upregulation of the rate of erythropoiesis anda reduction in hepcidin level to make more iron available for increasederythropoietic activity. This maladaptive response results in ironoverload due to the reduced hepcidin levels, which lead to enhancedamounts of active ferroportin, allowing increased absorption of dietaryiron, as described above. Red cells in thalassemia have a shortenedhalf-life because of the toxicity of an imbalanced ratio of alpha- andbeta-hemoglobin-subunits. Also in the treatment of beta-thalassemia theuse of hepcidin mimetic peptides has been described, the therapeuticrationale being based on the increase of hepcidin activity leading toiron restriction and reduction of iron mediated damage in red cells.Administration of hepcidin mimetic peptides to the th3/+ mouse, a modelof non-transfusion dependent beta-thalassemia resulted in relief ofineffective erythropoiesis, increased red cell survival time andimprovement of anemia. In this model the prevention of iron overload dueto reduction in the absorption of dietary iron turned out as anadditional benefit of the hepcidin mimetic therapy (Gardenghi et al,2010; Casu et al 2013).

The described therapeutic approaches are based on a direct involvementinto the disturbed iron metabolism pathway by directly acting via theprimary regulator hepcidin by providing a hepcidin mimetic or a hepcidinagonist, i.e. acting in the sense of a kind of hepcidin substitute orsupply. The approach is based on the therapeutic rationale to treat ironoverload, i.e. excess serum iron level, by inhibiting ferroportin, viathe hepcidin-inactivation mechanism, thus blocking excessive ironabsorption.

Further known iron overload related diseases are diseases associatedwith ineffective erythropoiesis such as the myelodysplastic syndromes(also known as MDS or myelodysplasia), polycythemia vera, etc.

Further, mutations in genes involved in sensing the systemic ironstores, such as hepcidin (Hamp1), hemochromatosis protein (HFE),hemojuvelin (HJV) and transferrin receptor 2 (TFR2) cause iron overloadin mice and men. Accordingly, diseases related to HFE and genemutations, chronic hemolysis associated diseases, sickle cell diseases,red cell membrane disorders, as well as Glucose-6-phosphatedehydrogenase deficiency (G6PD deficiency), erythrpoietic porphyria andFriedrich's Ataxia can be mentioned. Further, subgroups of iron overloadcomprise transfusional iron overload, iron intoxication, pulmonaryhemosiderosis, osteopenia, insulin resistense, African iron overload,Hallervordan Spatz disease, hyperferritinemia, ceruloplasmin deficiency,neonatal hemochromatosis and red blood cell disorders comprisingthalassemia, alpha thalassemia, thalassemia intermedia, sickle celldisease and myelodyplastic syndrome are included.

Further disease and/or disorders and/or diseased conditions associatedwith elevated iron levels include, but are not limited to, diseases withelevated iron level, comprising ataxia, Friedrich's ataxia, age-relatedmacular degeneration, age-related cataract, age-related retinal diseasesand neurodegenrative disease, whereby such neurodegenrative diseasecomprises Alzheimer's disease, Parkinson's disease, pantothenatekinase-associated neurodegeneration, restless leg syndrome andHuntington's disease,

Hepcidin is a host defense peptide, representing a component of theinnate immune system that responds to invading organisms.

It has been described that many bacteria are highly dependent on asupply of iron from the host (so-called siderophilic organisms) and haveevolved mechanisms to capture iron from the local tissues. The abilityto limit the amount of iron available to such organisms byferroportin-inhibitors may represent effective adjunctive therapy. Onesuch siderophilic organism is Vibrio vulnificus, which causes rare butextremely severe infections in coastal communities, often in subjectswith undiagnosed iron overload. Studies in animals that have beeninoculated with a lethal dose of Vibrio vulnificus have demonstratednearly 100% survival in response to treatment with hepcidin mimeticpeptides, inactivating ferroportin, regardless of whether treatment isstarted before or after the infection is initiated (Arezes et al 2015).

As known hepcidin mimetics the so-called minihepcidins can be mentioned,described for example in WO 2013/086143. Minihepcidins are small-sizedsynthetic peptide analogues of the hepcidin N-terminus which is crucialfor hepcidin interaction with ferroportin. Minihepcidins have beendeveloped on the basis that the first 9 amino acids of hepcidin(DTHFPICIF) have been found to be sufficient for in vitro activity(measured as ferroportin-GFP degradation). Minihepcidins have a modifiedhepcidin-9 amino acid sequence to exhibit improved resistance toproteolysis and enhanced biophysical interaction with ferroportin.Minihepcidins are described to be useful for the treatment of human ironoverload conditions caused by hepcidin deficiency.

WO 2015/069660 describes methods for increasing hepcidin expression fortreating iron overload disorders by decreasing non-transferrin boundiron (NTBI) by administering a modified iron binding/releasingtransferrin.

All the described compounds which act as hepcidin agonists, hepcidinmimetics or ferroportin inhibitor etc. are relatively high molecularweight compounds, in particular those which are obtainable predominantlyby genetic engineering. Various further approaches on the basis ofbiomolecular interactions and biomolecules have been described. Thedisadvantage is the complex preparation and high sensitivity of suchbiomolecular compounds. In particular methods on the basis offerroportin antibodies are not sufficiently efficient as theantibody-inhibited ferroportin is permanently reproduced by the organismand the inhibition is thus not sufficiently long-lasting to achieve thedesired therapeutic effect.

Low molecular weight compounds which play a part in iron metabolism andcan have an inhibiting or promoting effect are also known.

For example WO 2008/151288, WO 2008/118790, WO 2008/115999, and WO2008/109840 describe compounds acting as divalent metal transporter-1(DMT1) inhibitors and their use for the treatment of iron disorders suchas thalassemia or hemochromatosis.

WO 2008/123093 relates to an agent for prevention or treatment of ironoverload disorders, comprising 22 beta-methoxyolean-12-ene-3 beta,24(4beta)-diol.

EP 1074254 and EP1072265 relate to the use of catechic- andflavonoid-structure plant polyphenols for treating iron overload.

WO 2011/029832 relates to thiazol and oxazol compounds which act ashepcidin antagonists and are thus described to be suitable in the usefor the treatment of iron deficiency diseases. Therein, hepcidinantagonistic activity is described to inhibit the inhibition offerroportin by hepcidin, which is the opposite effect as has been foundby the inventors of the present invention for the novel thiazol andoxazol compounds as described herein.

Chemical compounds based on the structures of the general formulae ofthe present invention have hitherto not been disclosed in connectionwith their activity as ferroportin inhibitors or for the use in theprophylaxis and treatment of iron metabolism disorders which areassociated with increased iron levels such as iron overload.

US 2004/0138268 A1, US 2011/0224136 A1, CN 103508957, WO 2006/062224 A1,WO 2015/051362 A1, EP 1953145 A1, WO 2009/154739 A2, GB 937878 A, WO2011/023722 A1, WO 2010/020556 A1, WO 2005/011685 A1, WO 00/56724 A1, WO2010/036632 A1, WO 2005/014576 A1, WO 2013/067578 A1, WO 2005/116355 A1or in Zou Yiquan et al. “Discovery of pyrazole as C-terminus ofselective BACE1 inhibitors”; Eur. J. of Medicinal Chemistry 68 (2013)270-283, Tussing-Humphreys et al. “Rethinking Iron Regulation andAssessment in Iron Deficiency, Anemia of Chronic Disease, and Obesity:Introducing Hepcidin” J. Academy of Nutrition and Dietetics (2012), Vol.122, No. 3, 391-400, Riordan et al. “Bleomycin analogs. Synthesis andproton NMR spectral assignments of thiazole amides related to bleomycinA2 (1)”; J. Heterocyclic Chem. 18, 1213 (1981), Hideaki Sasaki“Synthesis of a novel bis(2,4′-bithiazole) derivative as aCo(II)-activated DNA cleaving agent”; Chem. Pharm. Bull. 42(8) 1685-1687(1994), and Ballell et al. “Fueling open-source drug discovery. 177small-molecule leads against tuberculosis”; ChemMedChem 2013, 8, 313-321describe compounds for different medical uses and mechanisms of action.

OBJECT

The object of the present invention was to provide, in particular, newtherapeutically effective compounds that can be used for an effectivetherapy for the prophylaxis and treatment of iron metabolism disorderswhich are associated with increased iron levels, such as in particulariron overload. In a further object, the new compounds should exhibit fewside effects and have a very low toxicity and good bioavailability andcompatibility. Moreover, these new compounds, in contrast to the knowniron chelating compounds, should be suitable to prevent the occurrenceof increased iron levels and thus the related disorders, instead ofremoving excess iron from the body when the iron overload has alreadyoccurred. In a further object the new compounds should have a definedstructure (stoichiometry) and should be preparable by simple synthesisprocesses, exhibit less sensitivity and improved long-lasting efficiencyas compared to the known biomolecular compounds, such as antibodies.

This goal was achieved by the development of the novel compoundsaccording to the formulae as defined herein, such as in particularformula (A-I), which have been found to act as ferroportin inhibitors,thus being suitable for the use in the inhibition of iron transport, andthus being effective in the prophylaxis and treatment of iron metabolismdisorders which are associated with increased iron levels, such as inparticular iron overload, as well as in the prophylaxis and treatment ofdiseases caused by a lack of hepcidin, diseases related to or caused byincreased iron levels or iron overload and diseases associated withineffective erythropoiesis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows Fpn inhibitor trigger ubiquitination and degradation of Fpnexpressed in a mouse macrophage cell line.

FIG. 2 shows representative iron efflux inhibition of Hepcidin (IC₅₀:0.086 μM) and Example Compound No. 127 (IC₅₀: 0.080 μM).

FIG. 3 shows serum iron reduction induced by hepcidin and ferroportininhibitor according to Example Compound 94 (Example Compound No. 94).FIG. 3A shows kinetic of serum iron in naïve C57BL/6 mice injected withsynthetic hepcidin (5 mg/kg) intraperitoneally (i.p.) for the indicatedtime. * ***—indicate statistically significant serum iron reductioncompared to PBS-treated mice. FIG. 3B shows serum iron levels in naïveC57BL/6 mice treated with the indicated amounts of either hepcidin(i.p.) or Example Compound 94 (Example Compound No. 94). (p.o.) for 3 h.

FIG. 4 shows dose-dependent block of iron absorption in anemic rats byFpn inhibitor Example Compound No. 55.

FIG. 5 shows complete correction of the elevated serum iron levels inb2m−/− mice by treatment with the ferroportin inhibitors ExampleCompound No. 40/methylcellulose (A.) and Example Compound No.94/cremophor EL (B.) for 3 h.

DESCRIPTION OF THE INVENTION

The inventors have surprisingly found that specific compounds having thegeneral structural formula (A-I) as defined herein, act as ferroportininhibitors, thus effectively inhibiting iron transport and accordinglybeing particularly suitable for the use as medicaments, in particularfor the use in the treatment and/or prophylaxis of diseases caused by alack of hepcidin, diseases associated with ineffective erythropoiesis oriron metabolism disorders leading to increased iron levels, such asparticularly iron overload states such as in particular thalassemia andhemochromatosis. Very particularly the new compounds turned out to besuitable for treating thalassemia and hemochromatosis. The new compoundsare also suitable for the treatment of diseases caused by pathologicallylow hepcidin-levels and for the use in the inhibition of iron transport.

Accordingly, the invention relates to novel compounds of general formula(A-I)

wherein

Het-2 is an optionally substituted bicyclic heteroaryl of the formula

wherein * indicates the binding site to A² and

R⁴ indicates 1, 2 or 3 optional substituents, which may independently beselected from the group consisting of

halogen,

cyano,

optionally substituted alkyl,

optionally substituted alkoxy, and

a carboxyl group;

X¹ is C, N, S or O;

X² is C or N;

X³ is C, N, S or O; and

X⁴ is C, N, or S

with the proviso that 1 to 3 heteroatoms X are present,

and wherein X¹, X³ and X⁴, when having the meaning of C or N, may carrya further substituent,

such as preferably hydrogen or a substituent as defined above forsubstituted heteroaryl;

R¹ is selected from the group consisting of

-   -   hydrogen and    -   optionally substituted alkyl;

Cycl is selected from the group consisting of

-   -   substituted aryl and    -   substituted or unsubstituted heteroaryl;

Q is

-   -   hydrogen or    -   C₁-C₄-alkyl, which may form a fused 5- or 6-membered ring with        Cycl;

n is 0 or an integer of 1 to 8, preferably n is 0 or 1 to 4, preferablyn is 0, 1, 2 or 3;

A¹ is

-   -   optionally substituted alkanediyl;

A² is

-   -   optionally substituted alkanediyl or    -   a direct bond;

R³ is

-   -   hydrogen, or    -   optionally substituted alkyl; or

A¹ and R³ together with the nitrogen atom to which they are bonded forman optionally substituted 4- to 6-membered mono- or bicyclic ring; or

R³ and A² together with the nitrogen atom to which they are bonded forman optionally substituted 4- to 7-membered ring;

and

Y² is C or N, wherein

-   -   both Y² may be C or    -   one Y² may be N and one Y² may be C;

or pharmaceutically acceptable salts thereof.

Therein and throughout the invention, the above-mentioned substituentgroups are defined as follows:

Optionally substituted alkyl preferably includes:

linear or branched alkyl preferably containing 1 to 8, more preferably 1to 6, particularly preferably 1 to 4, even more preferred 1, 2 or 3carbon atoms.

Optionally substituted alkyl further includes cycloalkyl containingpreferably 3 to 8, more preferably 5 or 6 carbon atoms.

Examples of alkyl residues containing 1 to 8 carbon atoms include: amethyl group, an ethyl group, an n-propyl group, an i-propyl group, ann-butyl group, an i-butyl group, a sec-butyl group, a t-butyl group, ann-pentyl group, an i-pentyl group, a sec-pentyl group, a t-pentyl group,a 2-methylbutyl group, an n-hexyl group, a 1-methylpentyl group, a2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a1-ethylbutyl group, a 2-ethylbutyl group, a 3-ethylbutyl group, a1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a 3,3-dimethylbutylgroup, a 1-ethyl-1-methylpropyl group, an n-heptyl group, a1-methylhexyl group, a 2-methylhexyl group, a 3-methylhexyl group, a4-methylhexyl group, a 5-methylhexyl group, a 1-ethylpentyl group, a2-ethylpentyl group, a 3-ethylpentyl group, a 4-ethylpentyl group, a1,1-dimethylpentyl group, a 2,2-dimethylpentyl group, a3,3-dimethylpentyl group, a 4,4-dimethylpentyl group, a 1-propylbutylgroup, an n-octyl group, a 1-methylheptyl group, a 2-methylheptyl group,a 3-methylheptyl group, a 4-methylheptyl group, a 5-methylheptyl group,a 6-methylheptyl group, a 1-ethylhexyl group, a 2-ethylhexyl group, a3-ethylhexyl group, a 4-ethylhexyl group, a 5-ethylhexyl group, a1,1-dimethylhexyl group, a 2,2-dimethylhexyl group, a 3,3-dimethylhexylgroup, a 4,4-dimethylhexyl group, a 5,5-dimethylhexyl group, a1-propylpentyl group, a 2-propylpentyl group, etc. Those containing 1 to6, preferably 1 to 4 carbon atoms, such as in particular methyl, ethyl,n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, and t-butyl arepreferred. C₁-C₃ alkyl, in particular, methyl, ethyl and i-propyl aremore preferred. Most preferred are C₁ and C₂ alkyl, such as methyl andethyl.

Cycloalkyl residues containing 3 to 8 carbon atoms preferably include: acyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexylgroup, a cycloheptyl group and a cyclooctyl group. A cyclopropyl group,a cyclobutyl group, a cyclopentyl group and a cyclohexyl group arepreferred. A cyclopentyl group and a cyclohexyl group are particularlypreferred.

Substituents of the above-defined optionally substituted alkylpreferably include 1 to 3 of the same or different substituents, morepreferably 1 or 2 of the same or different substituents, selected, forexample, from the group consisting of: optionally substitutedcycloalkyl, as defined above, hydroxy, an oxo-group (═O), carboxy,halogen, as defined below, cyano, alkoxy, as defined below, optionallysubstituted acyl, as defined below, optionally substituted acyloxy, asdefined below, optionally substituted aryl, as defined below, optionallysubstituted heteroaryl, as defined below, optionally substitutedheterocyclyl, as defined below, optionally substituted amino, as definedbelow, optionally substituted alkyl, aryl or heterocyclylsulfonyl(R—SO₂—), as defined below as well as an alkylene group such as inparticular a methylene-group, forming for example amethylene-substituted ethyl-group (CH₃—(C═CH₂)— or

wherein * indicates the binding site). Preferably the 1 to 3substituents of alkyl are selected from optionally substitutedcycloalkyl, hydroxy, oxo (═O), carboxy, optionally substituted acyloxy,halogen, optionally substituted aryl, optionally substituted heteroaryl,optionally substituted heterocyclyl, optionally substituted amino,optionally substituted alkyl, aryl or heterocyclylsulfonyl (R—SO₂—) andan alkylene group such as in particular a methylene-group. Morepreferred are 1 to 3 substituents of alkyl, selected from optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl and an alkylene group such as in particular amethylene-group. More preferred is one substituent of alkyl. Mostpreferred is one substituent of alkyl, which is optionally substitutedaryl or optionally substituted heteroaryl as defined below.

Within the meaning of the present invention, halogen includes fluorine,chlorine, bromine and iodine, preferably fluorine or chlorine, mostpreferred is fluorine.

Examples of a linear or branched alkyl residue substituted by halogenand containing 1 to 8 carbon atoms include:

a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, achloromethyl group, a dichloromethyl group, a trichloromethyl group, abromomethyl group, a dibromomethyl group, a tribromomethyl group, a1-fluoroethyl group, a 1-chloroethyl group, a 1-bromoethyl group, a2-fluoroethyl group, a 2-chloroethyl group, a 2-bromoethyl group, adifluoroethyl group such as a 1,2-difluoroethyl group, a1,2-dichloroethyl group, a 1,2-dibromoethyl group, a 2,2-difluoroethylgroup, a 2,2-dichloroethyl group, a 2,2-dibromoethyl group a2,2,2-trifluoroethyl group, a heptafluoroethyl group, a 1-fluoropropylgroup, a 1-chloropropyl group, a 1-bromopropyl group, a 2-fluoropropylgroup, a 2-chloropropyl group, a 2-bromopropyl group, a 3-fluoropropylgroup, a 3-chloropropyl group, a 3-bromopropyl group, a1,2-difluoropropyl group, a 1,2-dichloropropyl group, a1,2-dibromopropyl group, a 2,3-difluoropropyl group, a2,3-dichloropropyl group, a 2,3-dibromopropyl group, a3,3,3-trifluoropropyl group, a 2,2,3,3,3-pentafluoropropyl group, a2-fluorobutyl group, a 2-chlorobutyl group, a 2-bromobutyl group, a4-fluorobutyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a4,4,4-trifluorobutyl group, a 2,2,3,3,4,4,4-heptafluorobutyl group, aperfluorobutyl group, a 2-fluoropentyl group, a 2-chloropentyl group, a2-bromopentyl group, a 5-fluoropentyl group, a 5-chloropentyl group, a5-bromopentyl group, a perfluoropentyl group, a 2-fluorohexyl group, a2-chlorohexyl group, a 2-bromohexyl group, a 6-fluorohexyl group, a6-chlorohexyl group, a 6-bromohexyl group, a perfluorohexyl group, a2-fluoroheptyl group, a 2-chloroheptyl group, a 2-bromoheptoyl group, a7-fluoroheptyl group, a 7-chloroheptyl group, a 7-bromoheptyl group, aperfluoroheptyl group, etc. Fluoroalkyl, difluoroalkyl andtrifluoroalkyl are mentioned in particular, and trifluoromethyl andmono- and di-fluoroethyl is preferred. Particularly preferred istrifluoromethyl and 2,2-difluoroethyl.

Examples of a cycloalkyl residue substituted by halogen and containing 3to 8 carbon atoms include: a 2-fluorocyclopentyl group, a2-chlorocyclopentyl group, a 2-bromocyclopentyl group, a3-fluorocyclopentyl group, a 3-chlorocyclopentyl group, a3-bromocyclopentyl group, a 2-fluorocyclohexyl group, a2-chlorocyclohexyl group, a 2-bromocyclohexyl group, a3-fluorocyclohexyl group, a 3-chlorocyclohexyl group, a3-bromocyclohexyl group, a 4-fluorocyclohexyl group, a4-chlorocyclohexyl group, a 4-bromocyclohexyl group, adi-fluorocyclopentyl group, a di-chlorocyclopentyl group, adi-bromocyclopentyl group, a di-fluorocyclohexyl group, adi-chlorocyclohexyl group, a di-bromocyclohexyl group, atri-fluorocyclohexyl group, a tri-chlorocyclohexyl group, atri-bromocyclohexyl group, etc.

Examples of a hydroxy-substituted alkyl residue include theabove-mentioned alkyl residues which contain 1 to 3 hydroxyl residuessuch as, for example, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,etc. Hydroxymethyl being preferred.

Examples of an oxo-substituted alkyl residue includes theabove-mentioned alkyl residues, wherein at least one carbon atom issubstituted by an oxo-group forming a carbonyl group [—(C═O)—] in thealkyl chain or an alkanoyl-group [alkyl-(C═O)—)], such as C₁ to C₆alkanoyl, such as formyl, acetyl, propionyl, butyryl, isobutyryl,valeryl, isovaleryl, pivaloyl, hexanoyl, etc. Preferred is anoxo-substitution of the alkyl residue in the form of a carbonyl-group[—(C═O)—] or an acetyl-group like [—(C═O)—CH₃] or [—(C═O)—CH₂—].

Examples of an alkoxy-substituted alkyl residue include theabove-mentioned alkyl residues which contain 1 to 3 alkoxy residues asdefined below such as, for example, methoxymethyl, ethoxymethyl,2-methoxyethylene, etc.

Examples of an acyl-substituted alkyl residue include theabove-mentioned alkyl residues which contain 1 to 3 acyl residues asdefined below.

Examples of an acyloxy-substituted alkyl residue include theabove-mentioned alkyl residues which contain 1 to 3, preferably 1acyloxy residues [—O—(C═O)—].

Examples of a cycloalkyl-substituted alkyl group include theabove-mentioned alkyl residues containing 1 to 3, preferably 1(optionally substituted) cycloalkyl group such as, for example:cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl cyclohexylmethyl,2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl2-cyclohexylethyl, 2- or 3-cyclopropylpropyl, 2- or 3-cyclobutylpropyl,2- or 3-cyclopentylpropyl, 2- or 3-cyclohexylpropyl, etc. Preferred arecyclopropylmethyl and cyclohexylmethyl.

Examples of an aryl-substituted alkyl group include the above-mentionedalkyl residues containing 1 to 3, preferably 1 (optionally substituted)aryl group, as defined below, such as, for example, phenylmethyl, 1- or2-phenylethyl, 2- or 3-phenylpropyl, etc., phenylmethyl, 1-phenylethyl,2-phenylethyl, and 2-phenylpropyl being preferred. Also particularlypreferred are alkyl groups, as defined above, which are substituted bysubstituted aryl, as defined below, in particular by phenyl beingsubstituted with 1 to 3, preferably 1 or 2 of the same of differentsubstituents, preferably selected from halogen, such as preferably F andCl, cyano, optionally substituted alkyl, such as preferably methyl,ethyl, halogen-substituted alkyl such as trifluoromethyl, optionallysubstituted alkoxy, such as methoxy, ethoxy, halogen-substituted alkoxysuch as difluoromethoxy, trifluoromethoxy, an optionally substitutedamino group such as amino (NH₂—) or mono- or di-alkylamino such aspreferably dimethylamino, an optionally substituted heterocyclyl group,such as pyrrolidinyl, alkyl-substituted piperazinyl, or morpholinyl, oran optionally substituted heterocyclylsulfonyl group, such asN-morpholinyl-sulfonyl, forming in particular alkyl-groups, which aresubstituted with substituted aryl according to the formulas

which are particularly preferred for R¹ and/or R².

Examples of a heterocyclyl-substituted alkyl group include theabove-mentioned alkyl residues containing 1 to 3, preferably 1(optionally substituted) heterocyclyl group, as defined below, which maybe substituted with 1 to 3, preferably with 1 substituent. Preferablythe heterocyclyl group as a substituent of alkyl is for example amorpholinyl group, a piperazinyl group, a piperidinyl group etc. Asdefined above, the heterocylcyl group may be substituted and a preferredsubstituent is an optionally substituted alkyl group, preferably amethyl or ethyl group or a trifluoromethyl group. Particularly preferredis a piperidinyl group and a methyl-substituted morpholinyl group.

Examples of a heteroaryl-substituted alkyl group include theabove-mentioned alkyl residues containing 1 to 3, preferably 1(optionally substituted) heteroaryl group, as defined below, such as,for example a pyridinyl, a pyridazinyl, a pyrimidinyl, a pyrazinyl, apyrazolyl, an imidazolyl, a benzimidazolyl, a thiophenyl, or an oxazolylgroup, such as pyridine-2-yl-methyl, pyridine-3-yl-methyl,pyridine-4-yl-methyl, 2-pyridine-2-yl-ethyl, 2-pyridine-1-yl-ethyl,2-pyridine-3-yl-ethyl, pyridazine-3-yl-methyl, pyrimidine-2-yl-methyl,pyrimidine-4-yl-methyl, pyrazine-2-yl-methyl, pyrazol-3-yl-methyl,pyrazol-4-yl-methyl, pyrazol-5-yl-methyl, imidazole-2-yl-methyl,imidazole-5-yl-methyl, benzimidazol-2-yl-methyl, thiophen-2-yl-methyl,thiophen-3-yl-methyl, 1,3-oxazole-2-yl-methyl.

Preferred is an alkyl group which is substituted with optionallysubstituted pyridazinyl, such as in particular pyridazin-3-yl-methyl andpyridazin-3-yl-ethyl, optionally substituted pyridinyl, such as inparticular optionally substituted pyridine-2-yl-methyl,pyridine-3-yl-methyl, pyridine-4-yl-methyl, 2-pyridine-2-yl-ethyl,2-pyridine-1-yl-ethyl, 2-pyridine-3-yl-ethyl, very particularlyoptionally substituted pyridine-2-yl-methyl and 2-pyridin-2-yl-ethyl,optionally substituted pyrazol-3-yl-methyl, pyrazol-4-yl-methyl,pyrazol-5-yl-methyl, pyrazol-3-yl-ethyl, pyrazol-4-yl-ethyl,pyrazol-5-yl-ethyl. Particularly preferred is substitutedpyridinyl-alkyl, such as substituted pyridinyl-methyl or substitutedpyridinyl-ethyl, wherein the 1, 2 or 3 substituents are selected fromhalogen, such as fluorine, C₁-C₃-alkyl, such as methyl, andtrifluoromethyl. Particularly preferred is fluorine substitutedpyridinyl-alkyl, such as fluorine substituted pyridinyl-methyl orfluorine substituted pyridinyl-ethyl. Most preferred is fluorinesubstituted pyridinyl-methyl according to formula

Examples of a heteroaryl-substituted alkyl group includes further inparticular a cyclo-alkyl residue as defined above, which is bound to theheteroaryl-substituent by forming a fused ring with theheteroaryl-substituent as defined above, preferably the fusedcyclo-alkyl-residue is cyclopentyl or cyclohexyl. Further, preferablythe fused heteroaryl-substitutent is pyridinyl, forming for examplefused rings such as cyclopenta-pyridinyl and cyclohexa-pyridinyl,according to the formulas

which are particularly preferred for R² or a group Cycl-[CQ]_(n),wherein Q is C₁-C₄-alkyl, which forms a fused 5- or 6-membered ring withCycl.

In each case the heterocyclyl-substituent of an alkyl-residue as definedherein may be substituted with 1 to 3, preferably 1 or 2 of the same ordifferent substituents, which are preferably selected from halogen, suchas preferably F and Cl, cyano, optionally substituted alkyl, such aspreferably methyl, ethyl, halogen-substituted alkyl such astrifluoromethyl and hydroxy-substituted alkyl such as hydroxymethyl,optionally substituted alkoxy, such as preferably methoxy and ethoxy, anoxo-group (═O), a heterocyclyl group as defined below, such as anN-morpholinyl group, an aminocarbonyl group, an optionally substitutedamino group, such as preferably amino (NH₂—) or mono- or di-alkylaminosuch as preferably dimethylamino.

Examples of an amino-substituted alkyl residue include theabove-mentioned alkyl residues containing 1 to 3, preferably 1(optionally substituted) amino group, as defined below, such as, forexample, aminoalkyl (NH₂-alkyl) or mono- or dialkylamino-alkyl, such asaminomethyl, 2-aminoethyl, 2- or 3-aminopropyl, methylaminomethyl,methylaminoethyl, methylaminopropyl, 2-ethylaminomethyl,3-ethylaminomethyl, 2-ethylaminoethyl, 3-ethylaminoethyl, etc. or analkyl group, which may be substituted with an optionally substitutedalkyloxycarbonylamino group such as a group according to formula

wherein R defines a substituent of alkyl as defined above, preferably aphenyl group, such group being particularly preferred for R³.

Throughout the invention, optionally substituted aryl preferablyincludes:

aromatic hydrocarbon residues containing 6 to 14 carbon atoms (excludingthe carbon atoms of the possible substituents), which may be monocyclicor bicyclic, including, for example: phenyl, naphthyl, phenanthrenyl andanthracenyl, which may optionally be substituted preferably by 1 to 3 ofthe same or different substituents (e.g. indicated as R⁶) selected fromhydroxy, halogen, as defined above, cyano, optionally substituted amino,as defined below, optionally substituted alkyl, as defined above,optionally substituted acyl, as defined below, and optionallysubstituted alkoxy, as defined below, optionally substituted aryloxy, asdefined below, optionally substituted heterocyclyloxy, as defined below,optionally substituted aryl, as defined herein, optionally substitutedheterocyclylyl, as defined below. Optionally substituted phenyl ispreferred, such as unsubstituted phenyl and phenyl which is substitutedwith 1 to 3, more preferably with 1 or 2 substituents R⁶, which may bethe same or different. The 1 to 3 phenyl substituents (e.g. indicated asR⁶) are in particular selected from the group consisting of heterocyclylas defined below, halogen as defined above such as in particular F,optionally substituted amino as defined below such as in particular(—NH₂) or mono- or dialkylamino with dimethylamino being preferred,cyano, optionally substituted alkoxy as defined below such as inparticular di-fluoromethoxy and trifluoromethoxy, and an optionallysubstituted sulfonyl-group which may form in particular a group

with * indicating the binding site of the substituted phenylsubstituent. Most preferred is halogen-substituted phenyl,alkoxy-substituted phenyl and hydroxyl-substituted phenyl. Theaforementioned substituents of phenyl are particularly preferred for thegroup “Cycl” in the formulae as defined herein with the meaning of asubstituted aryl group being substituted phenyl.

Examples of an alkyl-substituted aryl group preferably include: aryl, asdescribed above which is substituted by straight-chain or branched alkylcontaining 1 to 8, preferably 1 to 4 carbon atoms, as described above.Toluoyl is the preferred alkylaryl.

Examples of a hydroxy-substituted aryl group preferably include: aryl,as described above, which is substituted by 1 to 3 hydroxyl residuessuch as, for example 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,2,4-di-hydroxyphenyl, 2,5-di-hydroxyphenyl, 2,6-di-hydroxyphenyl,3,5-di-hydroxyphenyl, 3,6-di-hydroxyphenyl, 2,4,6-tri-hydroxyphenyl,etc.

Examples of a halogen-substituted aryl group preferably include: aryl,as described above, which is substituted by 1 to 3 halogen atoms suchas, for example 2-chloro- or fluorophenyl, 3-chloro- or fluorophenyl,4-chloro- or fluorophenyl, 2,4-di-(chloro- and/or fluoro)phenyl,2,5-di-(chloro- and/or fluoro)phenyl, 2,6-di-(chloro- and/orfluoro)phenyl, 3,5-di-(chloro- and/or fluoro)phenyl, 3,6-di-(chloro-and/or fluoro)phenyl, 2,4,6-tri-(chloro- and/or fluoro)phenyl, etc.

Examples of an alkoxy-substituted aryl group preferably include: aryl,as described above, which is substituted by 1 to 3 alkoxy residues, asdescribed below, such as preferably 2-methoxyphenyl, 3-methoxyphenyl,4-methoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl,2,4-di-methoxyphenyl, etc., as well as di-fluoromethoxyphenyl andtrifluoromethoxyphenyl.

Throughout the invention, optionally substituted heterocyclyl preferablyincludes: Saturated or unsaturated mono- or bicyclic 4- to 8-memberedheterocyclic residues containing 1 to 3, preferably 1 to 2 same ordifferent hetero atoms, selected from N, O and S and which mayoptionally be substituted preferably by 1 to 3 substituents, whereinreference may be made to the definition of possible substituents foroptionally substituted heterocyclyl. 4-, 5- and 6-membered saturated orunsaturated, mono- or bicyclic optionally substituted heterocyclicresidues are preferred, and examples comprise azetidinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl,tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, etc., such asazetidin-1-yl, azetidin-2-yl, azetidin-3-yl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydro-thiophen-2-yl,tetrahydro-thiophen-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,pyrrolidin-3-yl, morpholin-1-yl, morpholin-2-yl, morpholin-3-yl,piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,piperazin-1-yl, piperazin-2-yl, tetrahydropyran-2-yl,tetrahydropyran-3-yl, tetrahydropyran-4-yl, etc., which may optionallybe condensed with aromatic rings. Particularly preferred are azetidinyl,pyrrolidinyl, piperidinyl, and morpholinyl residues. Particularlypreferred are the following heterocyclic residues, which may besubstituted as defined above:

(with X being N, O or S, preferably S), which are particularly preferredfor A¹, and

being particularly preferred for R¹ and/or R², and

which is particularly preferred as a substituent for an aryl group.

Preferred substituents of heterocyclyl-residues comprise an alkyl-groupsuch as preferably methyl and ethyl, a hydroxyl-group, and an oxo-group(═O).

Throughout the invention, optionally substituted heteroaryl includes:

heteroaromatic hydrocarbon residues containing 4 to 9 ring carbon atoms,which additionally preferably contain 1 to 3 of the same or differentheteroatoms from the series S, O, N in the ring and therefore preferablyform 5- to 12-membered heteroaromatic residues which may preferably bemonocyclic but also bicyclic. Preferred aromatic heterocyclic residuesinclude: pyridyl (pyridinyl), pyridyl-N-oxide, pyridazinyl, pyrimidyl,pyrazinyl, thienyl (thiophenyl), furyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, thiazolyl, oxazolyl or isoxazolyl, indolizinyl, indolyl,benzo[b]thienyl, benzo[b]furyl, indazolyl, quinolyl, isoquinolyl,naphthyridinyl, quinazolinyl, quinoxalinyl. 5- or 6-membered aromaticheterocycles are preferred, such as from the group of 5-memberedheteroaryl, for example thiazolyl such as thiazol-2-yl, 2-thiazol-2-yl,2-thiazol-4-yl, thienyl (thiophenyl) such as thien-3-yl, pyrazolyl suchas 1-pyrazol-4-yl, 3-pyrazol-5-yl, imidazolyl such as imidazole-2-yl,2-imidazol-4-yl, 1-imidazol-4-yl, triazolyl such as 1-triazol-3-yl,1-triazol-4-yl, such as 1,2,4-triazol-3-yl or 1,2,3-triazol-4-yl,oxazolyl such as 2-oxazol-4-yl, 2-oxazol-5-yl, oxadiazolyl such as1,2,4-oxadiazol-3-yl and from the group of 6-membered heteroaryl, forexample pyridyl (pyridinyl) such as pyrid-1-yl, pyrid-2-yl, pyrid-3-yl,pyrid-4-yl, 2-pyrid-4-yl, 2-pyrid-6-yl, 3-pyrid-5-yl (pyridin-1-yl,pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-pyridin-4-yl,2-pyridin-6-yl, 3-pyridin-5-yl, pyrimidin-2-yl, pyrimidin-4-yl,pyrimidin-5-yl, and from the group of bicyclic heteroaromatic residuesin particular benzimidazolyl such as benzimidazol-2-yl,benzimidazol-4-yl, benzimidazol-5-yl, as well as benzimidazol-pyridinylaccording to formula

or benzoxazol-2-yl according to formula

or benzimidazol forming a fused ring with a heterocyclyl residue, asdefined above.

The aforementioned heteroaryl-groups may have one or more, preferably 1to 3, more preferably 1 or 2 same or different substituents, which arein particular selected from halogen, such as preferably F and Cl, cyano,optionally substituted alkyl as defined above, such as preferablymethyl, ethyl, n-propyl, i-propyl, halogen-substituted alkyl such asdifluoromethyl or trifluoromethyl, hydroxy-substituted alkyl such ashydroxymethyl, aminocarbonyl-substituted alkyl such asaminocarbonylmethyl, carboxyl-substituted alkyl such as carboxylmethyl,an alkenyl group such as propenyl, optionally substituted alkoxy, suchas preferably methoxy and ethoxy, a hydroxyl group (—OH), an oxo-group(═O), a carboxyl group [—(C═O)—OH], a heterocyclyl group as definedabove, such as a N-morpholinyl group, an aminocarbonyl group, such asNH₂—(C═O)—, an optionally substituted amino group, such as preferablyamino (NH₂—) or mono- or di-alkylamino such as preferably dimethylamino.

In particular, examples of an alkyl-substituted heteroaryl grouppreferably include: heteroaryl, as described above, which is substitutedby linear or branched, optionally substituted alkyl containing 1 to 8,preferably 1 to 4 carbon atoms, as described above, such as inparticular methylimidazolyl such as in particular N-methylimidazolyl,methylbenzimidazolyl such as in particular N-methylbenzimidazolyl,5-methylbenzimidazolyl, 4-trifluoromethylbenzimidazolyl,5-trifluoromethylbenzimidazolyl, N-aminocarbonylmethylbenzimidazolyl,N-carboxylmethylaminocarbonyl, N-methylpyrazolyl, 1(N),5-dimethylpyrazolyl, methylpyridinyl such as 2-methylpyridin-3-yl,2-methylpyridin-4-yl, 3-methylpyridin-2-yl, 3-methylpyridin-3-yl,3-methylpyridin-4-yl, 4-methylpyridin-2-yl, 5-methylpyridin-2-yl,6-methylpyridin-2-yl etc., dimethylpyridinyl such as3,5-dimethylpyridin-2-yl, 4,6-dimethylpyridin-3-yl,trifluoromethylpyridinyl, in particular 3- or4-trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-3-yl,3-hydroxymethylpyridin-2-yl, 5-methylpyrimidin-2-yl, etc.

Examples of a halogen-substituted heteroaryl group preferably include:heteroaryl, as described above, which is substituted by 1 to 3,preferably 1 or 2 halogen atoms such as preferably by F and/or Cl,including in particular fluoropyridinyl such as 3-fluoro-pyridin-2-yl,4-fluoro-pyridin-2-yl, 5-fluoro-pyridin-2-yl, 6-fluoro-pyridin-2-yl,3-chloro-pyridin-2-yl, 4-chloro-pyridin-2-yl, 5-chloro-pyridin-2-yl,6-chloro-pyridin-2-yl, 2-fluoro-pyridin-3-yl, 4-fluoro-pyridin-3-yl,5-fluoro-pyridin-3-yl, 6-fluoro-pyridin-3-yl, 2-chloro-pyridin-3-yl,4-chloro-pyridin-3-yl, 5-chloro-pyridin-3-yl, 6-chloro-pyridin-3-yl,2-fluoro-pyridin-4-yl, 3-fluoro-pyridin-4-yl, 5-fluoro-pyridin-4-yl,6-fluoro-pyridin-4-yl, 2-chloro-pyridin-4-yl, 3-chloro-pyridin-4-yl,5-chloro-pyridin-4-yl, 6-chloro-pyridin-4-yl, etc., di-fluoropyridinylsuch as 3,5-di-fluoropyridin-2-yl, fluoro-chloro-pyridinyl such as3-chloro-5-fluoro-pyridin-2-yl, etc.

Examples of a halogen- and alkyl-substituted heteroaryl group preferablyinclude: heteroaryl, as described above, which is substituted by 1 to 3halogen atoms such as preferably by F and/or Cl, and 1 to 3 linear orbranched, optionally substituted alkyl-residues as described above, suchas in particular 3-fluoro-6-methylpyridin-2-yl,3-chloro-5-trifluoromethylpyridin-2-yl.

Further preferred examples of substituted heteroaryl-groups include:

methoxypyridinyl such as 3-, 4-, 5- or 6-methoxypyridin-2-yl, 2-, 4-, 5-or 6-methoxypyridin-3-yl, 2-, 3-, 5- or 6-methoxypyridin-4-yl, etc.,hydroxypyridinyl such as 3-, 4-, 5- or 6-hydroxypyridin-2-yl, 2-, 4-, 5-or 6-hydroxypyridin-3-yl, 2-, 3-, 5- or 6-hydroxypyridin-4-yl, etc.,oxo-pyridinyl such as 6-oxo-1,6-dihydropyridin-2-yl,2-oxo-1,2-dihydropyridin-3-yl etc., aminopyridinyl such as6-dimethylaminopyridin-3-yl, aminocarbonylpyridinyl such as6-aminocarbonylpyridin-3-yl, cyanopyridinyl such as 3-, 4-, 5- or6-cyanopyridin-2-yl, 2-, 4-, 5- or 6-cyanopyridin-3-yl, 2-, 3-, 5- or6-cyanopyridin-4-yl, etc., as well as 2-morpholin-4-yl-pyridin-4-yl.

With respect to the meaning of R⁴ as 1 to 3, preferably 1 or 2 same ordifferent substituents of a bicyclic heteroaryl group Het-2 according toany of the formulae as defined herein said heteroaryl-substituents arepreferably selected from halogen, such as preferably F and Cl, cyano,optionally substituted alkyl as defined above, such as preferablymethyl, ethyl, n-propyl, i-propyl, halogen-substituted alkyl such asdifluoromethyl or trifluoromethyl, aminocarbonyl-substituted alkyl suchas aminocarbonylmethyl, carboxyl-substituted alkyl such ascarboxylmethyl, optionally substituted alkoxy, such as preferablymethoxy and ethoxy and a carboxyl group [—(C═O)—OH]. It is mostpreferred, that R⁴ indicates 1 or 2 same or different substituentsselected from F, Cl, cyano, optionally substituted alkyl such as methyland trifluoromethyl, aminocarbonyl-substituted alkyl such asaminocarbonylmethyl, carboxyl-substituted alkyl such as carboxylmethyl,optionally substituted alkoxy, such as methoxy and a carboxyl group[—(C═O)—OH].

With respect to the meaning of R⁵ as 1 to 4, preferably 1 to 3, morepreferably 1 or 2 same or different substituents of a heteroaryl groupCycl according to any of the formulae as defined herein saidheteroaryl-substituents are preferably selected from halogen, such aspreferably F and Cl, cyano, optionally substituted alkyl as definedabove, such as preferably methyl, ethyl, n-propyl, i-propyl,halogen-substituted alkyl such as difluoromethyl or trifluoromethyl,hydroxy-substituted alkyl such as hydroxymethyl, optionally substitutedalkoxy, such as preferably methoxy and ethoxy, an oxo-group (═O), aheterocyclyl group as defined above, such as a N-morpholinyl group, anaminocarbonyl group such as NH₂—(C═O)—, an optionally substituted aminogroup, such as preferably amino (NH₂—) or mono- or di-alkylamino such aspreferably dimethylamino. It is most preferred, that R⁵ indicates 1 or 2same or different substituents selected from F, Cl, cyano, optionallysubstituted alkyl such as methyl, trifluoromethyl, and hydroxymethyl,optionally substituted alkoxy, such as methoxy, an oxo-group (═O),forming for example an oxo-substituted heteroaryl of the formula

a heterocyclyl group such as a N-morpholinyl group, an aminocarbonylgroup such as NH₂—(C═O)—, an optionally substituted amino group, such asdi-alkylamino such as dimethylamino.

Optionally substituted acyl here and hereinafter includes: formyl(—CH(═O)), optionally substituted aliphatic acyl (alkanoyl=alkyl-CO,wherein reference may be made to the foregoing definition of optionallysubstituted alkyl with respect to the alkyl group), optionallysubstituted aromatic acyl (aroyl=aryl-CO—, wherein reference may be madeto the foregoing definition of optionally substituted aryl with respectto the aryl group), optionally substituted heteroaromatic acyl(heteroaroyl=heteroaryl-CO—, wherein reference may be made to theforegoing definition of optionally substituted heteroaryl with respectto the heteroaryl group), or heterocyclic acyl(heterocycloyl=heterocyclyl-CO—, wherein reference may be made to theforegoing definition of optionally substituted heterocyclyl with respectto the heterocyclyl group). Aliphatic acyl=alkanoyl=alkyl-CO— ispreferred.

Optionally substituted amino according to the invention preferablyincludes: amino (—NH₂), optionally substituted mono- or dialkylamino(alkyl-NH—, (alkyl)₂N—), wherein with respect to “alkyl” reference canbe made to the definition of optionally substituted alkyl above. Furtherincluded are optionally substituted mono- or diarylamino, mono- ordiheteroarylamino and mono- or diheterocyclylamino radicals or mixedoptionally substituted alkylarylamino, alkylheteroarylamino andalkylheterocyclylamino radicals, wherein reference can be made to theabove definitions of optionally substituted alkyl, aryl, heteroaryl andheterocyclyl. According to the present invention an amino group furtherincludes a group —NH—.

Optionally substituted amino is preferably optionally substituted mono-or dialkylamino (alkyl-NH—, (alkyl)₂N—), in particular with 1 to 8,preferably 1 to 6, more preferably 1 to 3 carbon atoms, as previouslymentioned. Most preferred optionally substituted amino is mono- ordimethylamino and mono- or diethylamino. Most preferred is an aminogroup (—NH₂) or (—NH—) and a dimethylamino group.

Throughout the invention, optionally substituted alkanediyl ispreferably a divalent straight-chained or branched alkanediyl radicalhaving from 1 to 7, preferably from 1 to 6, more preferably from 1 to 4,carbon atoms, which can optionally carry from 1 to 3, preferably 1 or 2substituents selected from the group consisting of halogen, hydroxy, anoxo group (forming a carbonyl or acyl group) and an amino group asdefined above. The following may be mentioned as preferred examples:methylene, ethane-1,2-diyl, ethane-1,1-diyl, propane-1,3-diyl,propane-1,1-diyl, propane-1,2-diyl, propane-2,2-diyl, butane-1,4-diyl,butane-1,2-diyl, butane-1,3-diyl, butane-2,3-diyl, butane-1,1-diyl,butane-2,2-diyl, butane-3,3-diyl, pentane-1,5-diyl, etc. Particularlypreferred is methylene, ethane-1,2-diyl, ethane-1,1-diyl,propane-1,3-diyl, propane-2,2-diyl, and butane-2,2-diyl. Most preferredare methylene and ethane-1,2-diyl.

A preferred substituted alkanediyl radical is a hydroxy-substitutedalkanediyl such as a hydroxyl-substituted ethanediyl, an oxo-substitutedalkanediyl such as an oxo-substituted methylene or ethanediyl radical,forming a carbonyl or an acyl (acetyl) group, a halogen substitutedalkanediyl group such as an alkanediyl group being substituted with oneor two halogen atoms selected from F and Cl, preferably2,2-di-fluoro-ethanediyl, or an alkanediyl group which is substitutedwith an oxo and an amino group, forming an aminocarbonyl group such aspreferably a group [—(C═O)—NH—].

According to the present invention the substituents R¹ and R² or arespective group —[CQ]_(n)-, wherein Q is C₁-C₄-alkyl, may together withthe nitrogen atom to which they are bonded form an optionallysubstituted 3- to 6-membered ring, which may optionally contain furtherheteroatoms. Therein, R¹ and R² (or the group —[CQ]_(n)-, wherein Q isC₁-C₄-alkyl) may preferably together with the nitrogen atom to whichthey are bonded form a 5- or 6-membered ring, which may contain furtherheteroatoms, preferably one further heteroatom selected from N and O.Therein it is most preferred that R¹ and R² (or the group —[CQ]_(n)-,wherein Q is C₁-C₄-alkyl) together with the nitrogen atom to which theyare bonded form a 6-membered ring, which contains no further heteroatom,forming an N-piperidinyl ring or a 6-membered ring, which contains onefurther heteroatom 0, forming an N-morpholinyl ring. In particular suchN-piperidinyl ring may be substituted with aryl or heteroaryl as definedabove, preferably with phenyl or piperidinyl, forming a biciclyc ringaccording to the formula

According to the present invention it is further possible that A¹,having the meaning of a linear or branched alkanediyl group as definedabove, and R³, having the meaning of an optionally substituted alkylgroup as defined above, together with the nitrogen atom to which theyare bonded form an optionally substituted 4- to 6-membered aliphaticmono- or bicyclic ring, which may be substituted with 1 to 3substituents as defined above, such as for example according to thefollowing formulas

(with X being N, O or S, preferably S), wherein

is preferred.

In the context of the present invention it is further possible that R³and A² together with the nitrogen atom to which they are bonded form anoptionally substituted 4- to 7-membered ring, wherein optionalsubstituents are preferably selected from heteroaryl as defined aboveand an oxo group. A heteroaryl substituent may then also form a fusedring with the 4- to 7-membered ring formed by R³ and A² together withthe nitrogen atom to which they are bonded. Examples include residuesaccording to the following formulas:

In a further aspect, the invention relates to novel compounds of generalformula (I)

whereinR¹ and R² are the same or different and are independently selected fromthe group consisting of

hydrogen,

optionally substituted alkyl,

optionally substituted aryl,

optionally substituted heteroaryl,

optionally substituted heterocyclyl, or

R¹ and R² together with the nitrogen atom to which they are bonded forman

optionally substituted 3- to 6-membered ring, which may optionallycontain further heteroatoms;

X¹ is O or S,

Y¹ is hydrogen, optionally substituted alkyl or halogen,

preferably hydrogen or C₁-C₃-alkyl, preferably hydrogen or methyl;

A¹ is optionally substituted alkanediyl;

A² is

optionally substituted alkanediyl,

a direct bond, or

a sulfonyl group (—SO₂—);

R³ is

hydrogen, or

optionally substituted alkyl; or

A¹ and R³ together with the nitrogen atom to which they are bonded forman optionally substituted 4- to 6-membered mono- or bicyclic ring; orR³ and A² together with the nitrogen atom to which they are bonded forman optionally substituted 4- to 7-membered ring; and

Ar is

optionally substituted aryl,

optionally substituted monocyclic heteroaryl, or

optionally substituted bicyclic heteroaryl, which may be fused with aring formed by

R³ and A² together with the nitrogen atom to which they are bonded;

or pharmaceutically acceptable salts thereof.

It is particularly preferred that the substitutents in the formula (I)above have the meaning as follows:

R¹ and R² are the same or different and are independently selected fromthe group consisting of

-   -   hydrogen,    -   optionally substituted alkyl, or    -   R¹ and R² together with the nitrogen atom to which they are        bonded form and optionally substituted 3- to 6-membered ring,        which may optionally contain further heteroatoms;

X¹ is O or S;

Y¹ is hydrogen or C₁-C₃-alkyl, such as preferably hydrogen or methyl;

A¹ is optionally substituted alkanediyl;

A² is

-   -   optionally substituted alkanediyl, or    -   a direct bond;

R³ is

-   -   hydrogen, or    -   C₁-C₃-alkyl; or

A¹ and R³ together with the nitrogen atom to which they are bonded forman optionally substituted 4-membered monocyclic ring; or

R³ and A² together with the nitrogen atom to which they are bonded forman optionally substituted 4- to 7-membered ring; and

Ar is optionally substituted bicyclic heteroaryl.

PREFERRED EMBODIMENTS Embodiment A-2

A further preferred embodiment of the present invention relates to novelcompounds according to formula (A-II)

wherein Cycl, Q, R¹, X¹, X², X³, X⁴, R³, A¹, A², R⁴ and n have themeaning as defined above for formula (A-I); or pharmaceuticallyacceptable salts thereof.

Embodiment A-3

A further preferred embodiment of the present invention relates to novelcompounds according to formula (A-I) and (A-II) as defined above,wherein Cycl is substituted or unsubstituted heteroaryl as definedabove. Therein, the heteroaryl may be substituted with 1 to 4,preferably 1 to 3, more preferably 1 or 2 substituents R⁵ as definedabove and as defined below in context with compounds according to any ofthe formulae (A-IIIa) (A-IIIb), (A-IVa), (A-IVb), (A-IVc) and (A-IVd).

Embodiments A-3a and A-3b

A further preferred embodiment of the present invention relates to novelcompounds according to formula (A-1) and (A-II) as defined above,wherein Cycl is a substituted or unsubstituted heteroaryl, which isselected from a substituted or unsubstituted pyridinyl, formingcompounds according to formula (A-IIIa) or (A-IIIb), respectively:

wherein Q, R¹, X¹, X², X³, X⁴, R³, A¹, A², Y², R⁴ and n have the meaningas defined above for formula (A-I) or (A-II), and whereinR⁵ indicates 1 to 4, preferably 1 to 3, more preferably 1 or 2 optionalsubstituents, which may independently be selected from the groupconsisting of

halogen, preferably F and Cl,

optionally substituted alkyl, preferably methyl, trifluoromethyl,hydroxymethyl,

hydroxy,

alkoxy, preferably methoxy,

an oxo group (═O), forming a substituted pyridinyl-group of the formula

an amino group, such as —NH₂, mono- or dialkylamino, preferablydialkylamino

an aminocarbonyl group, preferably NH₂—(C═O)—,

cyano, and

a heterocyclyl group, preferably a morpholinyl-group,

or pharmaceutically acceptable salts thereof.

Embodiments A-4a and A-4b

A further preferred embodiment of the present invention relates to novelcompounds according to formula (A-IVa) and (A-IVb):

wherein Q, R¹, X¹, X², X³, X⁴, R³, A¹, A², Y², R⁴ and n have the meaningas defined above for formula (A-I), (A-II) or (A-IIIa) and (A-IIIb) andwhereinR⁵ has the meaning as defined above for formula (A-IIIa) and (A-IIIb),respectively;or pharmaceutically acceptable salts thereof.

It is particularly preferred that in any of the formulae (A-IIIa),(A-IIIb), (A-IVa) or (A-IVb) R⁵ indicates 1 to 3, more preferably 1 or 2substituents, even more preferred 1 substituent, which may independentlyhave the meaning as defined above.

Embodiments A-4c and A-4d

A further preferred embodiment of the present invention relates to novelcompounds according to the formulae (A-IIIa), (A-IIIb), (A-IVa) or(A-IVb), wherein R⁵ indicates 1 substituent, forming compounds accordingto the formula (A-IVc) and (A-IVd), respectively:

wherein Q, R¹, X¹, X², X³, X⁴, R³, A¹, A², Y², R⁴ and n have the meaningas defined above for formula (A-I), (A-II), (A-IIIa), (A-IIIb), (A-IVa)and (A-IVb) and whereinR⁵ has the meaning as defined above for formula (A-IIIa), (A-IIIb),(A-IVa) and (A-IVb), respectively;or pharmaceutically acceptable salts thereof.

Preferably in any of the aforementioned embodiments the one or moresubstituents R⁵ are independently selected from the group consisting of

halogen, preferably F and Cl,

optionally substituted alkyl, preferably methyl, trifluoromethyl,hydroxymethyl,

hydroxy, and

alkoxy, preferably methoxy.

More preferably in any of the aforementioned embodiments the one or moresubstituents R⁵ are independently selected from the group consisting of

halogen, preferably F and Cl, and

optionally substituted alkyl, preferably methyl, trifluoromethyl,hydroxymethyl.

Even more preferably in any of the aforementioned embodiments the one ormore substituents R⁵ are independently selected from the groupconsisting of

halogen, preferably F and Cl, most preferred being F.

Embodiment A-5

A further preferred embodiment of the present invention relates to novelcompounds according to formula (A-1) and (A-II) as defined above,wherein Cycl is a substituted aryl as defined above, which issubstituted with 1 to 3, preferably 1 or 2 substituents selected fromthe group consisting of

-   -   hydroxy,    -   halogen, preferably F and Cl, preferably F,    -   cyano,    -   optionally substituted alkyl,    -   optionally substituted amino, such as (—NH₂) or mono- or        dialkylamino, preferably dimethylamino,    -   optionally substituted acyl,    -   optionally substituted alkoxy, preferably methoxy,        di-fluoromethoxy and trifluoromethoxy,    -   optionally substituted aryloxy,    -   optionally substituted heterocyclyloxy,    -   optionally substituted aryl, and    -   optionally substituted heterocyclylyl, preferably optionally        substituted pyrrolininyl, morpholinyl, and piperazinyl,    -   an optionally substituted sulfonyl-group, such as preferably        heterocyclyl-substituted sulfonyl, preferably of the formula

such as preferably with 1 to 3, preferably 1 or 2 substituents R⁶ asdefined above and as defined below in context with compounds accordingto any of the formulae (A-Va) and (A-Vb);or pharmaceutically acceptable salts thereof.

Embodiments A-5a and A-5b

A further preferred embodiment of the present invention relates to novelcompounds according to formula (A-I) and (A-II) as defined above,wherein Cycl is a substituted aryl, which is selected from a substitutedphenyl, forming compounds according to formula (A-Va) or (A-Vb),respectively:

wherein Q, R¹, X¹, X², X³, X⁴, R³, A¹, A², Y², R⁴ and n have the meaningas defined above for formula (A-I) and (A-II) and whereinR⁶ has the meaning as defined above and in particular indicates 1 to 3,preferably 1 or 2 substituents, more preferably 1 substituent, selectedfrom the group consisting of

-   -   hydroxy,    -   halogen, preferably F and Cl, preferably F,    -   cyano,    -   optionally substituted alkyl,    -   optionally substituted amino, such as (—NH₂) or mono- or        dialkylamino, preferably dimethylamino,    -   optionally substituted acyl,    -   optionally substituted alkoxy, preferably methoxy,        di-fluoromethoxy and trifluoromethoxy,    -   optionally substituted aryloxy,    -   optionally substituted heterocyclyloxy,    -   optionally substituted aryl, and    -   optionally substituted heterocyclylyl, preferably optionally        substituted pyrrolininyl, morpholinyl, and piperazinyl,    -   an optionally substituted sulfonyl-group, such as preferably        heterocyclyl-substituted sulfonyl, preferably of the formula

-   -   or pharmaceutically acceptable salts thereof.

More preferably R⁶ has the meaning of 1 or 2 substituents, preferably R⁶indicates 1 substituent, selected from the group consisting of

-   -   hydroxy,    -   halogen, preferably F and Cl, preferably F,    -   cyano,    -   optionally substituted alkyl,    -   optionally substituted amino, such as (—NH₂) or mono- or        dialkylamino, preferably dimethylamino,    -   optionally substituted alkoxy, preferably methoxy,        di-fluoromethoxy and trifluoromethoxy,    -   optionally substituted heterocyclylyl, preferably optionally        substituted pyrrolininyl, morpholinyl, and piperazinyl, and    -   an optionally substituted sulfonyl-group, such as preferably        heterocyclyl-substituted sulfonyl, preferably of the formula

Even more preferably R⁶ indicates 1 substituent selected from the groupconsisting of

-   -   halogen, preferably F and Cl, preferably F,    -   cyano,    -   optionally substituted amino, such as (—NH₂) or mono- or        dialkylamino, preferably dimethylamino,    -   optionally substituted alkoxy, preferably methoxy,        di-fluoromethoxy and trifluoromethoxy,    -   optionally substituted heterocyclylyl, preferably optionally        substituted pyrrolininyl, morpholinyl, and piperazinyl, and    -   an optionally substituted sulfonyl-group, such as preferably        heterocyclyl-substituted sulfonyl, preferably of the formula

Further Embodiments A-6

Further preferred embodiments of the present invention relate to novelcompounds according to any one of the aforesaid embodiments or accordingto any of the formulae (A-I), (A-II), (A-IIIa), (A-IIIb), (A-IVa),(A-IVb), (A-IVc), (A-IVd), (A-Va) and (A-Vb) as defined above, orpharmaceutically acceptable salts thereof, wherein

Embodiment (A-6a) X¹ is N

and wherein one or two further heteroatoms X (X², X³, X⁴) are present,and wherein

X² is C or N; X³ is C, N, S or O; and X⁴ is C or N,

forming a group

wherein * indicates the binding site to the aminocarbonyl-group and **indicates the binding site to the A¹-group;with the proviso that in case of two further heteroatoms both areselected to be N or one is N and one (except X²) is O;and wherein X³ and X⁴, when having the meaning of C or N, may carry afurther substituent, such as preferably hydrogen (with X⁴═C) or asubstituent as defined above for substituted heteroaryl.

Embodiment (A-6b) X¹ is N, X² is C and X³ is 0; and X₄ is C or N,

forming a group

such as preferably a group

Embodiment (A-6b-1

or a group

Embodiment (A-6b-2

wherein * indicates the binding site to the aminocarbonyl-group and **indicates the binding site to the A¹-group; and whereinX⁴ (being C or N) may carry a further substituent, such as preferablyhydrogen (with X⁴═C) or a substituent as defined above for substitutedheteroaryl.

Embodiment (A-6c) X¹ is N, X² is C and X³ is S; and

X₄ is C or N, preferably C,forming a group

wherein * indicates the binding site to the aminocarbonyl-group and **indicates the binding site to the A¹-group;and whereinX⁴ may carry a further substituent, such as preferably hydrogen (withX⁴═C) or a substituent as defined above for substituted heteroaryl.

Embodiment (A-6d)

X² and X³ are both N,forming a group

wherein * indicates the binding site to the aminocarbonyl-group and **indicates the binding site to the A¹-group; and whereinX¹ and X⁴ are C;and wherein X¹ and/or X⁴ independently may carry hydrogen or a furthersubstituent, such as preferably a substituent as defined above forsubstituted heteroaryl.

Embodiment (A-6e) X¹ is C, and

X², X³ and X⁴ are N,forming a group

wherein * indicates the binding site to the aminocarbonyl-group and **indicates the binding site to the A¹-group; and whereinX¹ may carry hydrogen or a further substituent such as preferably asubstituent as defined above for substituted heteroaryl.

Embodiment (A-6f)

X¹, X² and X⁴ are N, and

X³ is C,

forming a group

wherein * indicates the binding site to the aminocarbonyl-group and **indicates the binding site to the A¹-group; and whereinX³ may carry hydrogen or a further substituent, such as a substituent asdefined above for substituted heteroaryl.

Embodiment (A-6g) X¹ is O, X² is C, X³ is N, and X⁴ is C,

forming a group

whereinY¹ indicates

-   -   hydrogen or    -   an optional substitutent to X⁴; and        * indicates the binding site to the aminocarbonyl-group and **        indicates the binding site to the A¹-group;

Embodiment (A-6h) X¹ is S, X² is C, X³ is N, and X⁴ is C,

forming a group

whereinY¹ indicates

hydrogen or

an optional substitutent to X⁴; and

* indicates the binding site to the aminocarbonyl-group and ** indicatesthe binding site to the A¹-group;

It is particularly preferred that in any of the embodiments describedherein the optional further substituents of X¹, X³ and X⁴ are alsoindicated as Y¹ or correspond to the substituent Y¹ as used herein andare selected from the group consisting of

-   -   halogen, preferably Cl and F, more preferably Cl, and    -   optionally substituted alkyl, such as linear or branched        C₁-C₃-alkyl, which may be substituted with 1 to 3 halogens or        with a methylene-group; such as preferably a methyl-group, an        iso-propyl-group, a CF₃-group or a methylene-substituted        ethyl-group

wherein * indicates the binding site.

Further Preferred Embodiments on the Basis of the Aforesaid EmbodimentsA-60 and A-6h Further Preferred Embodiment 2a

A further preferred embodiment of the present invention relates to novelcompounds according to the aforesaid embodiment A-6g and the formula (I)as defined above, wherein X is O, forming compounds according to formula(IIa):

wherein R¹, R², Y¹, R³, A¹, A² and Ar have the meaning as defined above;or pharmaceutically acceptable salts thereof.

Further Embodiment 2b

A further preferred embodiment of the present invention relates to novelcompounds according to the aforesaid embodiment A-6h and the formula (I)as defined above, wherein X is S, forming compounds according to formula(lib):

wherein R¹, R², Y¹, R³, A¹, A² and Ar have the meaning as defined abovefor formula (I) and as defined in context with any one of theembodiments described herein; or pharmaceutically acceptable saltsthereof.

Further Embodiment 3

A further preferred embodiment of the present invention relates to anyone of the compounds as defined above as embodiment A-6g and A-6h,embodiment 2a and embodiment 2b, wherein at least one of R¹ and R² is alinear alkyl group, as defined above, which is substituted with a cyclicgroup “Cycl”, designated as R^(2*); forming compounds according toformula (III):

wherein “Cycl” is selected from

-   -   optionally substituted aryl, as defined above,    -   optionally substituted heteroaryl, as defined above, and    -   optionally substituted heterocyclyl, as defined above,

preferably optionally substituted aryl or heteroaryl, as defined above;

-   -   n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3        such as 1, 2 or 3, more preferred 1; and the remaining of R¹ or        R² (designated as R^(1*)) is selected from    -   hydrogen,    -   optionally substituted alkyl, as defined above,

preferably hydrogen and optionally substituted alkyl, as defined above;and X¹, Y¹, R³, A¹, A² and Ar have the meaning as defined in formula (I)and as defined in context with any one of the embodiments describedherein; or pharmaceutically acceptable salts thereof.

Embodiment 3a

Another particularly preferred embodiment (3a) of the present inventionrelates to compounds as defined herein as embodiment A-6g and A-6h,embodiment 2a, embodiment 2b and embodiment 3 and in particular tocompounds according to formula (III) above, wherein at least one of R¹and R² is a linear alkyl group, as defined above, which is substitutedwith a cyclic group “Cycl”, designated as R^(2*); which is selected fromoptionally substituted aryl, as defined above, such as in particular anoptionally substituted phenyl group forming compounds according toformula (IIIa)

wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3such as 1, 2 or 3, more preferred 1; and the phenyl-ring may optionallybe substituted with 1 to 3, preferably 1 or 2, preferably 1 substituentsas defined above, preferably the substituents of the phenyl ring areselected from halogen and hydroxy; and the remaining of R¹ or R²(designated as R^(1*)) has the meaning as defined above, particularly asdefined for formula (I) and as defined in context with embodiment 3above; and X¹, Y¹, R³, A¹, A² and Ar have the meaning as defined informula (I) and as defined in context with any one of the embodimentsdescribed herein; or pharmaceutically acceptable salts thereof.

Embodiment 3b

Another preferred embodiment (3b) of the present invention relates tocompounds as defined herein as embodiment A-6g and A-6h, embodiment 2a,embodiment 2b, embodiment 3 and embodiment 3a and in particular tocompounds according to formula (III) above, wherein at least one of R¹and R² is a linear alkyl group, as defined above, which is substitutedwith a cyclic group “Cycl” being an optionally substituted heterocyclicgroup as defined above, “Het-1”, forming compounds according to formula(IIIb)

with Het-1 being selected from

-   -   an optionally substituted, optionally fused 5- to 6-membered        heteroaryl, as defined above, or    -   an optionally substituted 5- or 6-membered aliphatic        heterocyclyl, preferably a 6-membered aliphatic heterocyclyl,        each as defined above,        wherein the Het-1 group contains 1 or 2 identical or different        heteroatoms selected from N, O and S, preferably selected from N        and 0, more preferably N; and        the Het-1 group may carry 1 to 3, preferably 1 or 2, preferably        1 substituents as defined above, preferably selected from        halogen, cyano, optionally substituted alkyl as defined above,        optionally substituted alkoxy, a hydroxyl group (—OH), an        oxo-group (═O), a carboxyl group [—(C═O)—OH], a heterocyclyl        group as defined above, an aminocarbonyl group, an optionally        substituted amino group;        n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3        such as 1, 2 or 3, more preferred 1; and the remaining of R¹ or        R² (designated as R^(1*)) has the meaning as defined above,        particularly as defined in formula (I) and as defined in context        with embodiment 3 above and        X¹, Y¹, R³, A¹, A² and Ar have the meaning as defined in        formula (I) and as defined in context with any one of the        embodiments described herein; or pharmaceutically acceptable        salts thereof.

Embodiment 3b-a

Another preferred embodiment (3b-a) of the present invention relates tocompounds according to embodiment 3b and according to formula (IIIb)above, wherein Het-1 is selected from an optionally substituted5-membered heteroaryl, as defined above, preferably an optionallysubstituted pyrazolyl, forming for example compounds according toformula (IIIb-a)

wherein R⁵ is hydrogen or alkyl as defined above, preferablyC₁-C₃-alkyl,n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as1, 2 or 3, more preferred 1; andthe remaining of R¹ or R² (designated as R^(1*)) has the meaning asdefined above, particularly as defined in formula (I) and as defined incontext with embodiment 3 and 3b above, and wherein the pyrazolyl ringmay carry 1 or 2 further substituents as defined above; andX¹, Y¹, R³, A¹, A² and Ar have the meaning as defined in formula (I) andas defined in context with any one of the embodiments described herein;or pharmaceutically acceptable salts thereof.

Embodiment 3b-b

Another preferred embodiment (3b-b) of the present invention relates tocompounds according to embodiment 3b and according to formula (IIIb)above, wherein Het-1 is selected from an optionally substituted5-membered heteroaryl, as defined above, preferably an optionallysubstituted imidazolyl, forming for example compounds according toformula (IIIb-b)

wherein R⁴ is hydrogen or alkyl as defined above, preferablyC₁-C₃-alkyl,n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3 such as1, 2 or 3, more preferred 1; and PG-71C1the remaining of R¹ or R² (designated as R^(1*)) has the meaning asdefined above, particularly as defined in formula (I) and as defined incontext with embodiment 3 and 3b above, and wherein the imidazolyl ringmay carry 1 or 2 further substituents as defined above; andX¹, Y¹, R³, A¹, A² and Ar have the meaning as defined in formula (I) andas defined in context with any one of the embodiments described herein;or pharmaceutically acceptable salts thereof.

Embodiment 3b-c

Another preferred embodiment (3b-c) of the present invention relates tocompounds according to embodiment 3b and according to formula (IIIb)above, wherein Het-1 is selected from an optionally substituted6-membered heteroaryl, as defined above, preferably an optionallysubstituted pyrimidinyl, forming for example compounds according toformula (IIIb-c)

wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3such as 1, 2 or 3, more preferred 1; and the remaining of R¹ or R²(designated as R^(1*)) has the meaning as defined above, particularly asdefined in formula (I) and as defined in context with embodiment 3 and3b above, and wherein the pyrimidinyl ring may carry 1 to 3, preferably1 or 2 further substituents as defined above; andX¹, Y¹, R³, A¹, A² and Ar have the meaning as defined in formula (I) andas defined in context with any one of the embodiments described herein;or pharmaceutically acceptable salts thereof.

Embodiment 3b-d

Another preferred embodiment (3b-d) of the present invention relates tocompounds according to embodiment 3b and according to formula (IIIb)above, wherein Het-1 is selected from an optionally substituted6-membered heteroaryl, as defined above, preferably an optionallysubstituted pyridazinyl, forming for example compounds according toformula (IIIb-d)

wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3such as 1, 2 or 3, more preferred 1; and the remaining of R¹ or R²(designated as R^(1*)) has the meaning as defined above, particularly asdefined in formula (I) and as defined in context with embodiment 3 and3b above, and wherein the pyridazinyl ring may carry 1 to 3, preferably1 or 2 further substituents as defined above; and X¹, Y¹, R³, A¹, A² andAr have the meaning as defined in formula (I) and as defined in contextwith any one of the embodiments described herein; or pharmaceuticallyacceptable salts thereof.

Embodiment 3b-e

Another particularly preferred embodiment (3b-e) of the presentinvention relates to compounds according to embodiment 3b and accordingto formula (IIIb) above, wherein Het-1 is selected from an optionallysubstituted 6-membered heteroaryl, as defined above, preferably anoptionally substituted pyridinyl, forming for example compoundsaccording to formula (IIIb-e)

wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3such as 1, 2 or 3, more preferred 1; and the remaining of R¹ or R²(designated as R^(1*)) has the meaning as defined above, particularly asdefined in formula (I) and as defined in context with embodiment 3 and3b above, and wherein the pyridinyl ring may carry 1 to 3, preferably 1or 2 further substituents as defined above; andX¹, Y¹, R³, A¹, A² and Ar have the meaning as defined in formula (I) andas defined in context with any one of the embodiments described herein;or pharmaceutically acceptable salts thereof.

Embodiment 3b-f

Another particularly preferred embodiment (3b-f) of the presentinvention relates to compounds according to embodiment 3b and accordingto formula (IIIb) above, wherein Het-1 is selected from a substitutedpyridinyl, forming compounds according to formula (IIIb-f)

wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3such as 1, 2 or 3, more preferred 1; and the remaining of R¹ or R²(designated as R^(1*)) has the meaning as defined above, particularly asdefined in formula (I) and as defined in context with embodiment 3 and3b above, andwherein R⁵ indicates 1 to 4, preferably 1 to 3, preferably 1 or 2, morepreferably 1 optional substituents, which may independently be selectedfrom

-   -   hydrogen    -   halogen, preferably Cl or F, more preferably F,    -   optionally substituted alkyl, preferably C₁-C₃-alkyl, such as        preferably methyl, or trifluoromethyl    -   hydroxy, and    -   alkoxy, preferably methoxy;        more preferably R⁵ indicates 1 to 3, preferably 1 or 2, more        preferably 1 substituent, which may independently be selected        from    -   hydrogen,    -   halogen, preferably Cl or F, more preferably F, and    -   optionally substituted alkyl, preferably C₁-C₃-alkyl, such as        preferably methyl, or trifluoromethyl; and        X¹, Y¹, R³, A¹, A² and Ar have the meaning as defined in        formula (I) and as defined in context with any one of the        embodiments described herein; or pharmaceutically acceptable        salts thereof.

Embodiment 3b-a

Another particularly preferred embodiment (3b-g) of the presentinvention relates to compounds according to embodiment 3b and accordingto formula (IIIb), in particular according to embodiment 3b-f andformula (IIIb-f), forming compounds according to formula (IIIb-g)

wherein n, the remaining of R¹ or R² (designated as R^(1*)) has themeaning as defined for embodiment 3b-f, and wherein R⁵ is selected from

-   -   halogen, preferably Cl or F, more preferably F,    -   optionally substituted alkyl, preferably C₁-C₃-alkyl, such as        preferably methyl, or trifluoromethyl    -   hydroxy,    -   alkoxy, preferably methoxy;        more preferably R⁵ is selected from    -   halogen, preferably Cl or F, more preferably F, and    -   C₁-C₃-alkyl, such as preferably methyl, or trifluoromethyl; and        X¹, Y¹, R³, A¹, A² and Ar have the meaning as defined in        formula (I) and in any one of the embodiments as described        herein, particularly as described in context with embodiment        (IIIb-f) above;        or pharmaceutically acceptable salts thereof.

It is further very particularly preferred that in the compounds asdefined in formula (A-I) and (I) as well as in embodiments A-2, A-3,A-3a, A-3b, A-4a, A-4b, A-4c, A-4d, A-5, A-5a, A-5b, A-6 and A-6a toA-6h and embodiments 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and3b-g the at least one of R¹ and R² being a linear, branched or cyclicalkyl group substituted with a cyclic group “Cycl”. Such linear,branched or cyclic alkyl group means a linear or branched alkyl group—[CQ]_(n)- with Q=H or C₁-C₄-alkyl, which is substituted with saidcyclic group “Cycl”. In particular when one of R¹ and R² is a branchedalkyl group —[CQ]_(n)- with Q=C₁-C₄-alkyl, it is possible and preferredthat the alkyl-group of Q forms a cyclic alkyl residue in the form of afused ring with the cyclic group “Cycl”. Accordingly said “linear,branched or cyclic alkyl residue (which is substituted with a cyclicgroup “Cycl”) is selected from

-   -   an optionally substituted linear or branched alkanediyl group,        as defined above, which is preferably selected from        -   methylene,        -   ethane-1,2-diyl,        -   ethane-1,1-diyl,        -   propane-1,3-diyl,        -   propane-1,1-diyl,        -   propane-1,2-diyl, and        -   propane-2,2-diyl; or    -   (in particular with Q being a C₁-C₄-alkyl forming) an optionally        substituted cycloalkyl group, as defined above, which is        preferably selected from        -   cyclopropane and        -   cyclohexane;    -   which in a further preferred embodiment may preferably form a        fused bicyclic ring with Cycl being a Het-1 group selected from        a 6-membered heteroaryl as defined above.

More preferred is an optionally substituted linear or branchedalkanediyl residue, as defined above.

Even more preferably such optionally substituted alkanediyl residue isselected from the group consisting of methylene, ethane-1,2-diyl,ethane-1,1-diyl and propane-2,2-diyl; more preferably methylene orethane-1,2-diyl; most preferred is methylene.

In each of the above mentioned embodiments A-2, A-3, A-3a, A-3b, A-4a,A-4b, A-4c, A-4d, A-5, A-5a, A-5b, A-6 and A-6a to A-6h and embodiments3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and 3b-g the remaining ofR¹ or R², designated as R^(1*), X¹, Y¹, R³, A¹, A² and Ar may have themeaning as defined in in formula (A-I) or (I) and as defined contextwith any one of the embodiments described herein, in particular asdefined in context with embodiment 2 above, and 4, 4a, 4b, 4c and 4dbelow.

Further Embodiment 4

A further embodiment of the present invention relates to any one of thecompounds as defined above, such as in particular compounds ofembodiment A-6g and A-6h and further embodiments on the basis thereof asdefined above, wherein Ar is an optionally substituted mono- or bicyclicheteroaryl, as defined above, “Het-2”, forming compounds according toformula (IV)

with Het-2 being selected from

-   -   an optionally substituted 5- or 6-membered monocyclic        heteroaryl, as defined above, and    -   an optionally substituted bicyclic heteroaryl, as defined above,        which may be fused with a ring formed by R³ and A² together with        the nitrogen atom to which they are bonded;        or pharmaceutically acceptable salts thereof.

Embodiment 4a

Another embodiment (4a) relates to compounds as defined herein, such asin particular compounds of embodiment A-6g and A-6h and furtherembodiments on the basis thereof as defined above and in particular tocompounds according to formula (IV) above, wherein Ar being anoptionally substituted mono- or bicyclic heteroaryl “Het-2” is selectedfrom an optionally substituted 5-membered monocyclic heteroaryl, asdefined above, forming for example compounds according to formula (IVa)

wherein X⁵ is S or N—R⁷ with R⁷ having the meaning as defined above forR⁵, in particular as R⁵ in embodiments 3b-a and 3b-b, and wherein the5-membered heteroaryl ring of Het-2 may carry 1 to 3 furthersubstituents, preferably 1 or 2 further substituents, more preferably 1further substituent, as defined above;or pharmaceutically acceptable salts thereof.

Embodiment 4b

Another embodiment (4b) relates to compounds as defined herein, such asin particular compounds of embodiment A-6g and A-6h and furtherembodiments on the basis thereof as defined above and in particular tocompounds according to formula (IV) above, wherein Ar being anoptionally substituted mono- or bicyclic heteroaryl “Het-2” is selectedfrom an optionally substituted 6-membered monocyclic heteroaryl, asdefined above, forming for example compounds according to formula (IVb)

wherein Y³ is C or N, and wherein the 6-membered heteroaryl ring ofHet-2 may carry 1 to 3 substituents, preferably 1 or 2 substituents,more preferably 1 substituent, as defined above; or pharmaceuticallyacceptable salts thereof.

Embodiment 4c

Another embodiment (4c) relates to compounds as defined herein, such asin particular compounds of embodiment A-6g and A-6h and furtherembodiments on the basis thereof as defined above and in particular tocompounds according to formula (IV) above, wherein Ar being anoptionally substituted mono- or bicyclic heteroaryl “Het-2” is selectedfrom an optionally substituted bicyclic heteroaryl, as defined above,forming for example compounds according to formula (IVc)

with

-   -   both Y² being C or    -   one Y² being N and one Y² being C, and        wherein the bicyclic heteroaryl ring of Het-2 may carry 1 to 3        substituents, preferably 1 or 2 substituents, more preferably 1        substituent, as defined above, and wherein the optionally        substituted bicyclic heteroaryl ring of Het-2 may be fused with        a ring formed by R³ and A² together with the nitrogen atom to        which they are bonded; or pharmaceutically acceptable salts        thereof.

Embodiment 4d

Another embodiment (4d) relates to compounds as defined herein, such asin particular compounds of embodiment A-6g and A-6h and furtherembodiments on the basis thereof as defined above and in particular tocompounds according to formula (IV) and (IVc) above, wherein Ar being anoptionally substituted mono- or bicyclic heteroaryl “Het-2” is selectedfrom an optionally substituted bicyclic heteroaryl, which is selectedfrom benzimidazolyl, as defined above, forming compounds according toformula (IVd)

wherein the benzimidazolyl ring of Het-2 may carry 1 to 3 substituents,preferably 1 or 2 substituents, more preferably 1 substituent, asdefined above, andwherein the benzimidazolyl ring of Het-2 may be fused with a ring formedby R³ and A² together with the nitrogen atom to which they are bonded;or pharmaceutically acceptable salts thereof.

In each of the above mentioned embodiments 4, 4a, 4b, 4c and 4d theremaining substituents R¹, R², X¹, Y¹, R³, A¹ and A² may have themeaning as defined in formula (I) and as defined in context with any oneof the embodiments described herein, in particular as defined in formula(I) and in context with embodiment 2 above, and embodiments 3, 3a, 3b,3b-a, 3b-b, 3b-c, 3b-d, 3b-e, 3b-f and 3b-g above.

FURTHER EMBODIMENTS Further Embodiment B-2a

A particularly preferred embodiment (B-2a) relates to compounds of theformula (B-IIa)

wherein 1 to 3 heteroatoms X (X¹, X², X³ and/or X⁴) are present, whereinX¹ to X⁴ may be the same or different and are independently selectedfrom the group consisting of C, N, S and O. Preferably in formula(B-IIa) 1 to 3 heteroatoms X are present, wherein

X¹ is C, N, S or O;

X² is C or N;

X³ is C, N, S or O; and

X⁴ is C, N, S or O, preferably X⁴ is C, N or S,

and wherein X¹, X³ and X⁴ with the meaning of C or N may carry a furthersubstituent.

Embodiment B-2a-a

Another particularly preferred embodiment (B-2a-a) relates to compoundsaccording to formula (B-IIa) above, wherein X¹ is N, forming a compoundof the formula (B-IIa-a)

wherein one or two further heteroatoms X (X², X³, X⁴) are present, andwherein

X² is C or N;

X³ is C, N, S or O; and

X⁴ is C or N;

with the proviso that in case of two further heteroatoms both areselected to be N or one is N and one (except X²) is 0; andwherein X³ and X⁴ with the meaning of C or N may carry a furthersubstituent, such as preferably hydrogen or a substituent as definedabove for substituted heteroaryl.

Embodiment B-2a-b

Another particularly preferred embodiment (B-2a-b) relates to compoundsaccording to formula (B-IIa) above, wherein X² and X³ are both N,forming a compound of the formula (B-IIa-b)

with X¹ and X⁴ being C; and wherein X¹ and/or X⁴ may carry hydrogen or afurther substituent, such as preferably a substituent as defined abovefor substituted heteroaryl.

Embodiment B-2a-c

Another particularly preferred embodiment (B-2a-c) relates to compoundsaccording to formula (B-IIa) or (B-IIa-a) above, wherein X¹ is N, X² isC and X³ is S, forming a compound of the formula (B-IIa-c)

wherein X⁴ is C or N, preferably C, which may carry a furthersubstituent, such as preferably hydrogen or a substituent as definedabove for substituted heteroaryl.

Embodiment B-2a-d

Another particularly preferred embodiment (B-2a-d) relates to compoundsaccording to formula (B-IIa) or (B-IIa-a) above, wherein X¹ is N, X² isC and X³ is O, forming a compound of the formula (IIa-d)

wherein X⁴ is C or N, and which may carry a further substituent, such aspreferably hydrogen or a substituent as defined above for substitutedheteroaryl; forming compounds according to formula (B-IIIa-d-1)

wherein X⁴ being C may carry hydrogen or a further substituent, andwhich is preferred; or forming compounds according to formula(B-IIIa-d-2)

wherein X⁴ being N may carry a further substituent.

Embodiment B-3b-e

Another particularly preferred embodiment (B-3b-e) of the presentinvention relates to compounds according to formula (B-IIIb-e)

wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3such as 1, 2 or 3, more preferred 1; and the remaining of R¹ or R²(designated as R^(1*)) has the meaning as defined in the embodimentsabove, particularly as defined for formula (I), and wherein thepyridinyl ring may carry 1 to 3, preferably 1 or 2 further substituentsas defined above, andR³, A¹, A² and Ar have the meaning as defined in context with any one ofthe embodiments described herein, and wherein Z has the meaning of aheterocyclic 5-membered ring as defined in formula (A-I)

and as defined in any one of the embodiments A-6a, A-6b, A-6b-1, A-6b-2,A-6c, A-6d, A-6e, A-6f, A-6g and A-6h, preferably as defined in formula(A-I) and in embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d.

Embodiment B-3b-f

Another particularly preferred embodiment (B-3b-f) of the presentinvention relates to compounds according to formula (B-IIIb-f)

wherein n is an integer of 1 to 8, preferably 1 to 4, preferably 1 to 3such as 1, 2 or 3, more preferred 1; and the remaining R¹ or R²(designated as R^(1*)) has the meaning as defined in the embodimentsabove, particularly as defined for formula (I), andwherein R⁵ indicates 1 to 4, preferably 1 to 3, preferably 1 or 2, morepreferably 1 optional substituents, which may independently be selectedfrom

-   -   halogen, preferably Cl or F, more preferably F,    -   optionally substituted alkyl, preferably C₁-C₃-alkyl, such as        preferably methyl, or trifluoromethyl    -   hydroxy,    -   alkoxy, preferably methoxy;        preferably R⁵ is selected from    -   halogen, preferably Cl or F, more preferably F, and    -   C₁-C₃-alkyl, such as preferably methyl, or trifluoromethyl; and        R³, A¹, A² and Ar have the meaning as defined in context with        any one of the embodiments described herein, and wherein Z has        the meaning of a heterocyclic 5-membered ring as defined in        formula (A-I)

and as defined in any one of the embodiments A-6a, A-6b, A-6b-1, A-6b-2,A-6c, A-6d, A-6e, A-6f, A-6g and A-6h, preferably as defined in formula(A-I) and in embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d.

Embodiment B-3b-q

Another very particularly preferred embodiment (B-3b-g) of the presentinvention relates to compounds according to formula (B-IIIb-g)

wherein n and the remaining of R¹ or R² (designated as R^(1*)) has themeaning as defined for embodiment B-3b-f, and wherein R⁵ is selectedfrom

-   -   halogen, preferably Cl or F, more preferably F,    -   optionally substituted alkyl, preferably C₁-C₃-alkyl, such as        preferably methyl, or trifluoromethyl    -   hydroxy,    -   alkoxy, preferably methoxy;        more preferably R⁵ is selected from    -   halogen, preferably Cl or F, more preferably F, and    -   C₁-C₃-alkyl, such as preferably methyl, or trifluoromethyl; and        R³, A¹, A² and Ar have the meaning as defined in context with        any one of the embodiments described herein, and wherein Z has        the meaning of a heterocyclic 5-membered ring as defined in        formula (A-I)

and as defined in any one of the embodiments A-6a, A-6b, A-6b-1, A-6b-2,A-6c, A-6d, A-6e, A-6f, A-6g and A-6h, preferably as defined in formula(A-I) and in embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d.

It is further very particularly preferred that in the compoundsaccording to formula (A-I) and as defined in embodiments A-2, A-3, A-3a,A-3b, A-4a, A-4b, A-4c, A-4d, A-5, A-5a, A-5b, A-6 and A-6a to A-6h andin embodiments B-3b-e, B-3b-f and B-3b-g the at least one of R¹ and R²being a linear, branched or cyclic alkyl group substituted with a cyclicgroup “Cycl”, including the group —[CQ]_(n)- with Q=H or C₁-C₄-alkyl,the resulting alkyl-residue is

-   -   an optionally substituted linear or branched alkanediyl group,        as defined above, which is preferably selected from        -   methylene,        -   ethane-1,2-diyl,        -   ethane-1,1-diyl,        -   propane-1,3-diyl,        -   propane-1,1-diyl,        -   propane-1,2-diyl, and        -   propane-2,2-diyl; or    -   (in particular with Q being a C₁-C₄-alkyl forming) an optionally        substituted cycloalkyl group, as defined above, which is        preferably selected from        -   cyclopropane and        -   cyclohexane;    -   which in a further preferred embodiment may preferably form a        fused bicyclic ring with Cycl being a 6-membered heteroaryl as        defined above.

More preferred is an optionally substituted alkanediyl residue, asdefined above. Even more preferably such optionally substitutedalkanediyl residue is selected from the group consisting of methylene,ethane-1,2-diyl, ethane-1,1-diyl and propane-2,2-diyl; more preferablymethylene or ethane-1,2-diyl; most preferred is methylene.

In each of the above mentioned embodiments B-3b-e, B-3b-f and B-3b-g theremaining of R¹ or R², designated as R^(1*), Z, R³, A¹, A² and Ar mayhave the meaning as defined in context with any one of the embodimentsdescribed herein.

Embodiment B-4c

Another particularly preferred embodiment (B-4c) relates to compounds asdefined herein and in particular to compounds according to formula(B-IVc)

with

-   -   both Y² being C or    -   one Y² being N and one Y² being C, and        wherein the bicyclic heteroaryl ring may carry 1 to 3        substituents, preferably 1 or 2 substituents, more preferably 1        substituent, as defined above (e.g. as defined for R⁴ above),        and wherein the optionally substituted bicyclic heteroaryl ring        may be fused with a ring formed by R³ and A² together with the        nitrogen atom to which they are bonded.        Z has the meaning of a heterocyclic 5-membered ring as defined        in formula (A-I)

and as defined in any one of the embodiments A-6a, A-6b, A-6b-1, A-6b-2,A-6c, A-6d, A-6e, A-6f, A-6g and A-6h, preferably as defined in formula(A-I) and in embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d.

Embodiment B-4d

Another very particularly preferred embodiment (B-4d) relates tocompounds as defined herein and in particular to compounds according(B-IVc) above, with the optionally substituted bicyclic heteroaryl beinga benzimidazolyl, as defined above, forming compounds according toformula (B-IVd)

wherein the benzimidazolyl ring may carry 1 to 3 substituents,preferably 1 or 2 substituents, more preferably 1 substituent, asdefined above (e.g. as defined for R⁴ above), andwherein the benzimidazolyl ring may be fused with a ring formed by R³and A² together with the nitrogen atom to which they are bonded, andZ has the meaning of a heterocyclic 5-membered ring as defined informula (A-I)

and as defined in any one of the embodiments A-6a, A-6b, A-6b-1, A-6b-2,A-6c, A-6d, A-6e, A-6f, A-6g and A-6h, preferably as defined in formula(A-I) and in embodiments A-6a, A-6b, A-6b-1, A-6b-2, A-6c, A-6d.

In each of the above mentioned embodiments B-4c and B-4d the remainingsubstituents R¹, R², Z, R³, A¹ and A² may have the meaning as defined incontext with any one of the embodiments described herein, in particularas defined in context with embodiments B-2a, B-2a-a, B-2a-b, B-2a-c andB-2a-d, as well as B-3b-e, B-3b-f and B-3b-g above.

It is further very particularly preferred that in the compoundsaccording to the present invention, such as in particular in thecompounds as defined in formula (A-I) and (I) and in embodiments A-2,A-3, A-3a, A-3b, A-4a, A-4b, A-4c, A-4d, A-5, A-5a, A-5b, A-6 and A-6ato A-6h and embodiments 2, 3, 3a, 3b, 3b-a, 3b-b, 3b-c, 3b-d, 3b-e,3b-f, 3b-g and 4, 4a, 4b, 4c and 4d as well as B-2a, B-2a-a, B-2a-b,B-2a-c, B-2a-d, B-3b-e, B-3b-f, B-3b-g, B-4c and B-4d above, A¹ and A²each are optionally substituted alkanediyl, as defined above, and arethe same or different and are independently selected from optionallysubstituted

-   -   methylene and    -   ethane-1,2-diyl, or    -   A¹ and R³ together with the nitrogen atom to which they are        bonded form an optionally substituted 4- to 6-membered mono- or        bicyclic ring, preferably a 4- or 6-membered mono- or bicyclic        ring, more preferably a 4-membered ring, as defined above.        Therein, more preferably    -   A¹ and A² are identical and are methylene,    -   A¹ and A² are identical and are ethane-1,2-diyl,    -   A¹ is methylene and A² is ethane-1,2-diyl,    -   A¹ is ethane-1,2-diyl and A² is methylene,    -   A¹ and R³ together with the nitrogen atom to which they are        bonded form an optionally substituted 4- to 6-membered aliphatic        mono- or bicyclic ring, preferably a 4-membered ring, and A² is        methylene, or    -   A¹ and R³ together with the nitrogen atom to which they are        bonded form an optionally substituted 4- to 6-membered aliphatic        mono- or bicyclic ring, preferably a 4-membered ring, and A² is        ethane-1,2-diyl; more preferably    -   A¹ and A² are identical and are ethane-1,2-diyl,    -   A¹ is ethane-1,2-diyl and A² is methylene or    -   A¹ and R³ together with the nitrogen atom to which they are        bonded form an optionally substituted 4-membered monocyclic        ring, and A² is ethane-1,2-diyl; even more preferably    -   A¹ and A² are identical and are ethane-1,2-diyl, or    -   A¹ is ethane-1,2-diyl and A² is methylene.

In further preferred embodiments of compounds according to the presentinvention, the individual substituents have the following definitions ineach case:

-   -   1. a) X¹ has the meaning of O, X³ has the meaning of N and X²        and X⁴ have the meaning of C and/or        -   b) X¹ has the meaning of N, X³ has the meaning of O and X²            and X⁴ have the meaning of C and/or        -   c) X¹ has the meaning of N, X³ has the meaning of S and X²            and X⁴ have the meaning of C and/or        -   d) X² and X⁴ have the meaning of N and one of X¹ and X³ has            the meaning of N and the remaining has the meaning of C            and/or        -   e) X¹ and X⁴ have the meaning of N, X² has the meaning of C            and X³ has the meaning of O; particularly preferred is a            heterocyclic 5-membered ring selected from oxazolyl,            thiazolyl, pyrazolyl, triazoly, oxadiazolyl as well as            isooxazolyl and isothiazolyl as defined in embodiments A-6b,            A-6b-1, A-6b-2, A-6c, A-6d, A-6e, A-6f, A-6g and A-6h.    -   2. Y¹ has the meaning of hydrogen, optionally substituted alkyl,        as defined above, preferably C₁, C₂ or C₃-alkyl, as defined        above, more preferably methyl.    -   3. n is 1    -   4. Q is H    -   5. Cycl is a group of the formula

wherein * indicates the binding site.

-   -   6. One of R¹ and R² is designated as R^(1*) and is hydrogen and        one of R¹ or R² is designated as R^(2*) and is selected from        hydrogen, and optionally substituted alkyl, as defined above,        preferably aryl-substituted alkyl and heteroaryl-substituted        alkyl, wherein the aryl and heteroaryl substituent each may        carry 1 to 3 substituents, as defined above. Particularly        preferred is that the at least one of R¹ or R² which is        designated as R^(2*) is optionally substituted aryl-methyl or        optionally substituted heteroaryl-methyl, most preferred is        optionally substituted heteroaryl-methyl and substituted phenyl.    -   7. A¹ and A² are optionally substituted alkanediyl and are the        same or different and are independently selected from        -   A¹ and A² are identical and are methylene,        -   A¹ and A² are identical and are ethane-1,2-diyl,        -   A¹ is methylene and A² is ethane-1,2-diyl,        -   A¹ is ethane-1,2-diyl and A² is methylene,        -   A¹ and R³ together with the nitrogen atom to which they are            bonded form an optionally substituted 4-membered monocyclic            ring, and A² is methylene, or        -   A¹ and R³ together with the nitrogen atom to which they are            bonded form an optionally substituted 4-membered monocyclic            ring, and A² is ethane-1,2-diyl.        -   Particularly preferred is that A¹ is methylene or            ethane-1,2-diyl and A² is ethane-1,2-diyl, or that A¹ and R³            together with the nitrogen atom to which they are bonded            form an optionally substituted 4-membered monocyclic ring            and A² is ethane-1,2-diyl.    -   8. R³ is hydrogen or optionally substituted alkyl, as defined        above, or A¹ and R³ together with the nitrogen atom to which        they are bonded form an optionally substituted 4-membered        monocyclic ring, preferably hydrogen.    -   9. Ar may be Het-1 as defined above, and is preferably        optionally substituted mono- or bicyclic heteroaryl, as defined        above, preferably optionally substituted benzimidazolyl as        defined above.

In a further preferred embodiment R¹ and R² are different, with onebeing hydrogen and the other one being an optionally substituted alkyl.More preferably, one of R¹ and R² is hydrogen and the other one is analkyl residue, which is substituted with

-   -   an optionally substituted aryl group as defined above,        preferably with an optionally substituted phenyl group as        defined above, or    -   with an optionally substituted heteroaryl group as defined        above, preferably with        -   an optionally substituted pyridinyl group,        -   an optionally substituted pyridazinyl group,        -   an optionally substituted pyrimidinyl group,        -   an optionally substituted pyrazolyl group,        -   an optionally substituted imidazolyl group.

Even more preferably, one of R¹ and R² is hydrogen and the other one isan alkyl residue, which is substituted with

-   -   an optionally substituted phenyl group,    -   an optionally substituted pyridinyl group,    -   an optionally substituted pyridazinyl group,    -   an optionally substituted pyrimidinyl group,

Still more preferably, one of R¹ and R² is hydrogen and the other one isan alkyl residue, which is substituted with

-   -   an optionally substituted phenyl group, preferably a substituted        phenyl group as defined above, or    -   an optionally substituted pyridinyl group,        wherein the optionally substituted pyridinyl group as a        substituent of an alkyl residue for one of R¹ and R² is most        preferred.

More preferably a halogen substituted pyridinyl group such as inparticular a pyridinyl group substituted with one fluorine substituentis selected, such as in particular a group according to formula

It is further preferred that in the embodiments as defined above Ar hasthe meaning of a bicyclic heteroaryl, such as in particularbenzimidazol, particularly benzimidazol-2-yl according to formula

It is further preferred that herein A¹ and A² each are optionallysubstituted alkanediyl, as defined above, such as very preferably withA¹ and A² being identical and methylene, or A¹ and A² being identicaland ethane-1,2-diyl, or A¹ being methylene and A² being ethane-1,2-diyl,or A¹ being ethane-1,2-diyl and A² being methylene, more preferably withA¹ and A² being identical and ethane-1,2-diyl, or with A¹ beingethane-1,2-diyl and A² being methylene, or wherein A¹ and R³ togetherwith the nitrogen atom to which they are bonded form an optionallysubstituted 4-membered monocyclic ring, and A² is ethane-1,2-diyl.

Particularly preferably the compounds according to the present inventionare selected from the compounds:

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210

211

212

213

214

215

218

219

220

223

226

227

228

230

231

233

236

239

242

243

244

247

249

250

251

252

253

255

256

257

258

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

or pharmaceutically acceptable salts thereof.

More preferred are the compounds according to formula (A-Ill), whereinCycl is an optionally substituted, optionally fused heteroaryl, such asExamples Nos.:

1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45,46, 47, 48, 49, 54, 55, 56, 57, 58, 59, 60, 61, 64, 76, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113, 114, 116,117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 131,132, 134, 135, 136, 137, 138, 141, 142, 144, 145, 148, 150, 151, 152,153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166,167, 169, 170, 171, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182,183, 184, 186, 187, 188, 189, 191, 192, 193, 194, 195, 196, 198, 199,205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 218, 219, 220,223, 226, 227, 228, 230, 231, 233, 236, 239, 242, 243, 244, 247, 249,250, 251, 252, 253, 255, 256, 257, 258, 261, 264, 265, 266, 267, 268,269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279 and 280.

More preferred are the compounds according to formula (A-Ill), whereinCycl is an optionally substituted, optionally fused 6-memberedheteroaryl, such as Examples Nos.:

1, 2, 3, 4, 5, 6, 7, 8, 12, 35, 36, 37, 38, 39, 40, 42, 43, 44, 45, 46,47, 48, 49, 54, 55, 56, 57, 58, 59, 61, 76, 79, 80, 81, 82, 83, 87, 89,90, 92, 93, 94, 96, 97, 98, 99, 101, 102, 103, 104, 105, 106, 108, 109,110, 111, 112, 113, 114, 116, 117, 118, 119, 120, 121, 122, 123, 124,125, 126, 127, 128, 129, 131, 132, 134, 135, 136, 137, 138, 141, 142,144, 145, 148, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160,161, 162, 163, 164, 165, 166, 167, 169, 170, 171, 173, 174, 175, 176,177, 178, 179, 180, 181, 182, 183, 184, 186, 187, 188, 189, 191, 192,193, 194, 195, 196, 198, 199, 205, 206, 207, 208, 209, 210, 211, 212,213, 214, 215, 218, 219, 220, 223, 226, 227, 228, 230, 231, 233, 236,239, 242, 243, 244, 247, 249, 250, 251, 252, 253, 255, 256, 257, 258,261, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276,277, 278, 279 and 280.

More preferred are the compounds according to formula (A-Ill), whereinCycl is an optionally substituted, optionally fused pyridinyl-group,such as Examples Nos.:

1, 2, 3, 4, 5, 6, 7, 8, 12, 35, 36, 37, 38, 39, 40, 42, 43, 45, 47, 48,49, 54, 55, 56, 57, 58, 59, 76, 79, 80, 81, 82, 83, 89, 90, 92, 94, 96,97, 98, 99, 101, 102, 103, 104, 105, 106, 108, 109, 110, 111, 112, 113,114, 116, 117, 118, 119, 120, 121, 123, 124, 125, 126, 127, 128, 131,132, 134, 135, 136, 137, 138, 141, 142, 144, 145, 148, 150, 151, 152,153, 154, 156, 157, 158, 159, 160, 162, 163, 164, 165, 166, 167, 169,170, 171, 173, 176, 177, 179, 180, 181, 184, 186, 187, 189, 191, 192,193, 194, 195, 196, 198, 199, 205, 206, 207, 208, 209, 210, 211, 212,213, 214, 215, 218, 219, 220, 223, 226, 227, 228, 230, 231, 233, 236,239, 242, 243, 247, 249, 250, 251, 252, 253, 255, 256, 257, 258, 264,265, 266, 267, 268, 269, 272, 273, 274, 275, 276, 277, 278, 279 and 280.

More preferred are the compounds according to formula (A-Ill), whereinCycl is an optionally substituted, optionally fused pyridinyl-group andhaving a 5-membered heterocyclic ring according to (A-6-b) forming anoxazolyl-ring, such as Examples Nos.:

126, 127, 128, 137, 141, 171, 173, 206, 207, 208, 223, 226, 227, 228,230, 233, 236, 239, 247, 249, 250, 251, 252, 253, 255, 256, 257, 258,264, 265, 266, 267, 268, 269, 272, 273;

and/or having a 5-membered heterocyclic ring according to (A-6-c)forming a thiazolyl-ring such as Examples Nos.:

12, 35, 36, 37, 38, 39, 40, 42, 43, 45, 47, 54, 55, 56, 57, 58, 59, 76,79, 80, 81, 82, 83, 89, 90, 94, 96, 97, 98, 99, 101, 102, 103, 104, 105,106, 108, 110, 112, 113, 114, 116, 118, 119, 120, 121, 123, 124, 125,134, 135, 148, 151, 152, 154, 157, 158, 159, 160, 163, 164, 165, 166,176, 177, 179, 180, 184, 186, 189, 193, 194, 195, 196, 199, 209, 211,212, 213, 214, 215, 218, 231, 242, 243, 274, 275, 276;

and/or having a 5-membered heterocyclic ring according to (A-6-g) and/or(A-6-h) forming an isooxazolyl or an isothiazolyl-ring such as ExamplesNos.:

1, 2, 3, 4, 5, 6, 7, 8 and 280;

and/or having a 5-membered heterocyclic ring according to (A-6-e) and/or(A-6-f) forming a triazolyl-ring such as Examples Nos.:

169, 170, 181, 277.

Further, compounds with one of R¹/R² being a fluorine-substitutedpyridinyl-group are preferred, such as Examples Nos.:

1, 2, 3, 4, 5, 6, 7, 8, 40, 94, 112, 113, 114, 118, 119, 120, 121, 125,126, 127, 128, 134, 135, 148, 151, 152, 154, 157, 163, 164, 165, 166,169, 176, 177, 179, 180, 181, 186, 193, 196, 199, 206, 208, 209, 211,212, 213, 214, 218, 223, 226, 227, 228, 230, 231, 233, 239, 242, 243,247, 249, 250, 251, 253, 255, 256, 257, 264, 265, 266, 267, 268, 269,272, 273, 274, 275, 276, 277, 279 and 280.

Pharmaceutically acceptable salts of the compounds according to theinvention include, for example, salts with suitable anions, such ascarboxylates, sulfonates, sulfates, chlorides, bromides, iodides,phosphates, tartrates, methane sulfonates, hydroxyethane sulfonates,glycinates, maleates, propionates, fumarates, toluene sulfonates,benzene sulfonates, trifluoroacetates, naphthalenedisulfonates-1,5,salicylates, benzoates, lactates, salts of malic acid, salts of3-hydroxy-2-naphthoic acid-2, citrates and acetates.

Pharmaceutically acceptable salts of the compounds according to theinvention further include, for example, salts with suitablepharmaceutically acceptable bases, such as, for example, salts withalkaline or alkaline-earth hydroxides, such as NaOH, KOH, Ca(OH)₂,Mg(OH)₂ etc., amine compounds such as ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, ethanolamine, diethanolamine,triethanolamine, methylglucamine, dicyclohexylamine,dimethylaminoethanol, procaine, dibenzylamine, N-methylmorpholine,arginine, lysine, ethylenediamine, N-methylpiperidin,2-amino-2-methyl-propanol-(1), 2-amino-2-methyl-propandiol-(1,3),2-amino-2-hydroxyl-methyl-propandiol-(1,3) (TRIS) etc.

Depending on their structure, the compounds according to the inventionmay exist in stereoisomeric forms (enantiomers, diastereomers) in thepresence of asymmetric carbon atoms. The invention therefore includesthe use of the enantiomers or diastereomers and the respective mixturesthereof. The pure-enantiomer forms may optionally be obtained byconventional processes of optical resolution, such as by fractionalcrystallisation of diastereomers thereof by reaction with opticallyactive compounds. Since the compounds according to the invention mayoccur in tautomeric forms, the present invention covers the use of alltautomeric forms.

The compounds provided according to the invention may be present asmixtures of various possible isomeric forms, in particular ofstereoisomers such as, for example, E- and Z-, syn and anti, as well asoptical isomers. The E-isomers and also the Z-isomers as well as theoptical isomers and any mixtures of these isomers are claimed.

The novel compounds of the present invention can be present in anamorphous, crystalline or partially crystalline form or they may also bepresent exist as hydrates.

The novel compounds according to formula (A-I) and its furtherembodiments, as defined above, have surprisingly been found to act asferroportin inhibitors and are thus suitable for the use as amedicament, such as in particular for the use as ferroportin inhibitors.

As already explained above, ferroportin is the iron transport protein,which is responsible for the uptake of the released iron via theintestine and its transfer into the blood circulation, thereby conveyingthe iron to the appropriate tissues and organs. Inactivation orinhibition of the ferroportin disables the export of the iron, therebyreducing the absorption of iron in the intestine. Ferroportin inhibitionin the sense of the present invention therefore includes the inhibitionof iron transport from the cells into the blood circulation and theinhibition of iron absorption in the intestine. Therein, the inhibitionof iron transport and/or iron reflux may be effected by different waysof mechanism, comprising for example inhibition of iron transportactivity of ferroportin and thus inhibition of iron reflux, triggeringinternalization, degradation and/or reduction of ferroportin,administering hepcidin agonists, i.e. compounds which compete withhepcidin or by compounds, which inhibit the binding of hepcidin toferroportin.

Ferroportin inhibition may be determined by measuring the inhibition offerroportin mediated iron transport activity in an iron response assay(BLAzer-Assay), as described in more detail in the Examples below.Further, ferroportin inhibition may be determined by measuringferroportin internalization and/or degradation in the FerroportinInternalization and Degradation Assay (FACS) or by examining theFerroportin Ubiquitination and Degradation, each as described in moredetail in the Examples below. Further, ferroportin inhibition may bedetermined by measuring the activity as an hepcidin agonist, for exampleby determining the Hepcidin binding capacity to ferroportin in theHepcidin Internalization Assay (J774), as described in more detail inthe Examples below. Further, ferroportin inhibition may be determined byconfirming the inhibition of hepcidin binding to ferroportin, forexample in the Biophysical Ferroportin-Hepcidin Binding Assay (Hep BindFP), as described in more detail in the Examples below. Further,ferroportin inhibition may be determined by determining the activity ofa compound regarding its ability to block iron export via ferroportin,for example with a test for measuring inhibition of iron efflux, asdescribed in more detail in the Examples below.

Ferroportin inhibition in the sense of the present invention can thus inparticular be defined by exhibiting a ferroportin inhibiting activity inat least one of the aforementioned test methods, shown in particular by:

Inhibition of ferroportin mediated iron transport activity in an ironresponse assay (Blazer Assay): IC₅₀ value [μm] of not more than 100(≤100), preferably not more than 50 (≤50), more preferably below 50(<50).

Ferroportin Internalization and Degradation Assay (FACS): EC₅₀ value[μm] of not more than 100 (≤100), preferably not more than 50 (≤50),more preferably below 50 (<50).

Ferroportin Ubiquitination and Degradation: visually inspected effect inWestern blots of “+ comparable to hepcidin”, “+/− intermediate effect”and “+/+/− stronger intermediate effect”, preferred is an effect “+” or“+/+/−”, most preferred is an effect “+”.

Hepcidin Internalization Assay (J774): IC₅₀ value of not more than 100(≤100), preferably not more than 50 (≤50), more preferably below 50(<50).

Biophysical Ferroportin-Hepcidin Binding Assay: IC₅₀ value of not morethan 100 (≤100), preferably not more than 50 (≤50), more preferablybelow 50 (<50).

Inhibition of Iron Efflux: IC₅₀ value of not more than 100 (≤100),preferably not more than 50 (≤50), more preferably below 50 (<50).

Ferroportin inhibition may further be determined in vivo models, asdescribed in more detail in the Examples below. Suitable in vivo modelsmay comprise, for example, examination of hypoferremia in naïve mice viameasurement of serum iron reduction; examination of prevention of ironabsorption in anemic rats via measurement of serum iron inhibition;examination of correction of hyperferremia in beta2-microglobulindeficient mice via measurement of serum iron reduction; examination ofprevention of iron overload in beta2-microglobulin deficient mice viameasurement of total iron in spleen or liver; examination of improvementof anemia, ineffective erythropoiesis and iron overload in a mouse modelof 3-thalassemia intermedia.

The activity of the compounds of the present invention as ferroportininhibitors can in particular be determined by the methods as describedin the Examples below.

As further already explained above, ferroportin inhibition may forexample be effected by hepcidin, which is thus an essential regulatingfactor of iron absorption, inhibiting ferroportin and thus blocking irontransport from the cells into the blood circulation and iron absorption.It has further surprisingly been found that several of the compounds asdefined herein act as hepcidin mimetics or hepcidin agonists, which isalso included by ferroportin inhibition in the sense of the presentinvention.

Accordingly, the compounds as defined in the present invention are alsosuitable for use in the inhibition of iron transport from the cells intothe blood circulation and the inhibition of iron absorption in theintestine, as well as for the use as hepcidin mimetics or hepcidinagonists.

Due to the activity of the compounds as defined herein as ferroportininhibitors, the compounds of the present invention are furtherparticularly suitable for the use in the inhibition of iron transportmediated by ferroportin and thereby for the use in the prophylaxisand/or treatment of iron metabolism disorders leading to increased ironlevels, of diseases related to or caused by increased iron levels,increased iron absorption or iron overload, such as in particular oftissue iron overload, of diseases associated with ineffectiveerythropoiesis, or of diseases caused by reduced levels of hepcidin.Further, the compounds of the present invention are suitable for the usein an adjunctive therapy by limiting the amount of iron available topathogenic microorganisms, such as the bacterium Vibrio vulnificus,thereby preventing or treating infections caused by said pathogenicmicroorganisms.

Therein, diseases being associated with, being related to, being causedby or leading to increased iron levels, increased iron absorption, ironoverload (e.g. tissue iron overload) or ineffective erythropoiesiscomprise thalassemia, hemoglobinopathy, such as hemoglobin E disease(HbE), hemoglobin H disease (HbH), haemochromatosis, hemolytic anemia,such as sickle cell anemia (sickle cell disease) and congenitaldyserythropoietic anemia.

Diseases being associated with, being related to, being caused by orleading to increased iron levels, increased iron absorption, ironoverload (e.g. tissue iron overload) further comprise neurodegenerativediseases, such as for example Alzheimer's disease and Parkinson'sdisease, wherein the compounds are considered to be effective bylimiting the deposition or increase of iron in tissue or cells.

The compounds of the present invention are further suitable for the usein the prophylaxis and/or treatment of formation of radicals, reactiveoxygen species (ROS) and oxidative stress caused by excess iron or ironoverload as well as in the prophylaxis and/or treatment of cardiac,liver and endocrine damage caused by excess iron or iron overload, andfurther in the prophylaxis and/or treatment of inflammation triggered byexcess iron or iron overload.

Diseases associated with ineffective erythropoiesis comprise inparticular myelodysplastic syndromes (MDS, myelodysplasia) andpolycythemia vera as well as congenital dyserythropoietic anemia.

Further diseases, disorders and/or diseased conditions comprise ironoverload caused by mutations in genes involved in sensing the systemiciron stores, such as hepcidin (Hamp1), hemochromatosis protein (HFE),hemojuvelin (HJV) and transferrin receptor 2 (TFR2), such as inparticular diseases related to HFE and HJV gene mutations, chronichemolysis associated diseases, sickle cell diseases, red cell membranedisorders, Glucose-6-phosphate dehydrogenase deficiency (G6PDdeficiency), erythrpoietic porphyria, Friedrich's Ataxia, as well assubgroups of iron overload such as transfusional iron overload, ironintoxication, pulmonary hemosiderosis, osteopenia, insulin resistense,African iron overload, Hallervordan Spatz disease, hyperferritinemia,ceruloplasmin deficiency, neonatal hemochromatosis and red blood celldisorders comprising thalassemia, including alpha thalassemia, betathalassemia and delta thalassemia, thalassemia intermedia, sickle celldisease and myelodyplastic syndrome.

Further diseases and/or disorders and/or diseased conditions associatedwith elevated iron levels include, but are not limited to, diseases withelevated iron level, comprising ataxia, Friedrich's ataxia, age-relatedmacular degeneration, age-related cataract, age-related retinal diseasesand neurodegenrative disease, such as pantothenate kinase-associatedneurodegeneration, restless leg syndrome and Huntington's disease,

The compounds of the present invention my further be suitable for theuse in the prophylaxis and treatment of diseases caused by a lack ofhepcidin.

In view thereof a further object of the present invention relates to amedicament containing one or more of the compounds as defined above,such as in particular a medicament for the prophylaxis and treatment inany of the indications, states, disorders or diseases as defined above.

A further object of the present invention relates to pharmaceuticalcompositions and medicaments comprising one or more of the compoundsaccording to the invention as defined above as well as optionally one ormore pharmacologically acceptable carriers and/or auxiliary substancesand/or solvents. A further object of the present invention relates topharmaceutical compositions and medicaments comprising one or more ofthe compounds according to the invention as defined above as well asoptionally one or more further pharmaceutically effective compounds. Thesaid pharmaceutical compositions contain, for example up to 99 weight-%or up to 90 weight-% or up to 80 weight-% or up to 70 weight-% of thecompounds of the invention, the remainder being each formed bypharmacologically acceptable carriers and/or auxiliaries and/or solventsand/or optionally further pharmaceutically active compounds.

Therein, the pharmaceutically acceptable carriers, auxiliary substancesor solvents are common pharmaceutical carriers, auxiliary substances orsolvents, including various organic or inorganic carrier and/orauxiliary materials as they are customarily used for pharmaceuticalpurposes, in particular for solid medicament formulations. Examplesinclude excipients, such as saccharose, starch, mannitol, sorbitol,lactose, glucose, cellulose, talcum, calcium phosphate, calciumcarbonate; binding agents, such as cellulose, methylcellulose,hydroxypropylcellulose, polypropyl pyrrolidone, gelatine, gum arabic,polyethylene glycol, saccharose, starch; disintegrating agents, such asstarch, hydrolyzed starch, carboxymethylcellulose, calcium salt ofcarboxymethylcellulose, hydroxypropyl starch, sodium glycol starch,sodium bicarbonate, calcium phosphate, calcium citrate; lubricants, suchas magnesium stearate, talcum, sodium laurylsulfate; flavorants, such ascitric acid, menthol, glycin, orange powder; preserving agents, such assodium benzoate, sodium bisulfite, paraben (for example methylparaben,ethylparaben, propylparaben, butylparaben); stabilizers, such as citricacid, sodium citrate, acetic acid and multicarboxylic acids from thetitriplex series, such as, for example, diethylenetriaminepentaaceticacid (DTPA); suspending agents, such as methycellulose, polyvinylpyrrolidone, aluminum stearate; dispersing agents; diluting agents, suchas water, organic solvents; waxes, fats and oils, such as beeswax, cocoabutter; polyethylene glycol; white petrolatum; etc.

Liquid medicament formulations, such as solutions, suspensions and gelsusually contain liquid carrier, such as water and/or pharmaceuticallyacceptable organic solvents. Furthermore, such liquid formulations canalso contain pH-adjusting agents, emulsifiers or dispersing agents,buffering agents, preserving agents, wetting agents, gelatinizing agents(for example methylcellulose), dyes and/or flavouring agents, forexample as defined above. The compositions may be isotonic, that is,they can have the same osmotic pressure as blood. The isotonicity of thecomposition can be adjusted by using sodium chloride and otherpharmaceutically acceptable agents, such as, for example, dextrose,maltose, boric acid, sodium tartrate, propylene glycol and otherinorganic or organic soluble substances. The viscosity of the liquidcompositions can be adjusted by means of a pharmaceutically acceptablethickening agent, such as methylcellulose. Other suitable thickeningagents include, for example, xanthan gum, carboxymethylcellulose,hydroxypropylcellulose, carbomer and the like. The preferredconcentration of the thickening agent will depend on the agent selected.

Pharmaceutically acceptable preserving agents can be used in order toincrease the storage life of the liquid composition. Benzyl alcohol canbe suitable, even though a plurality of preserving agents including, forexample, paraben, thimerosal, chlorobutanol and benzalkonium chloridecan also be used.

The above-mentioned pharmaceutical compositions are suitable, forexample, for intravenous, intraperitoneal, intramuscular, intravaginal,intrabuccal, percutaneous, subcutaneous, mucocutaneous, oral, rectal,transdermal, topical, intradermal, intragasteral or intracutaneousapplication and are provided, for example, in the form of pills,tablets, enteric-coated tablets, film tablets, layer tablets, sustainedrelease formulations for oral, subcutaneous or cutaneous administration(in particular as a plaster), depot formulations, dragees,suppositories, gels, salves, syrup, granulates, suppositories,emulsions, dispersions, microcapsules, microformulations,nanoformulations, liposomal formulations, capsules, enteric-coatedcapsules, powders, inhalation powders, microcrystalline formulations,inhalation sprays, epipastics, drops, nose drops, nose sprays, aerosols,ampoules, solutions, juices, suspensions, infusion solutions orinjection solutions etc.

A further object of the present invention relates to medicaments orcombined preparations containing one or more of the compounds as definedabove and at least one further pharmaceutically active compound, such asin particular a compound for the prophylaxis and treatment of ironoverload and the associated symptoms, preferably an iron-chelatingcompound, or a compound for the prophylaxis and treatment of any of thestates, disorders or diseases as defined above, such as in particular apharmaceutically active compound for the prophylaxis and treatment ofthalassemia, haemochromatosis, neurodegenerative diseases (such asAlzheimer's disease or Parkinson's disease) and the associated symptoms.

A further object of the present invention relates to the use of thecompounds as defined above per se, in a combination therapy (fixed doseor free dose combinations for sequential use) with one or two otheractive ingredients (drugs). Such combination therapy comprisesco-administration of the compounds of the present invention with the atleast one additional pharmaceutically active compound (drug).Combination therapy in a fixed dose combination therapy comprisesco-administration of the compounds of the present invention with the atleast one additional pharmaceutically active compound in a fixed-doseformulation. Combination therapy in a free dose combination therapycomprises co-administration of the compounds of the present inventionand the at least one additional pharmaceutically active compound in freedoses of the respective compounds, either by simultaneous administrationof the individual compounds or by sequential use of the individualcompounds distributed over a time period. The at least one additionalpharmaceutically active compound (drug) comprises in particular drugsfor reducing iron overload (e.g. Tmprss6-ASO) or iron chelators, inparticular curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamineand/or deferiprone, or antioxidants such as n-acetyl cysteine,anti-diabetics such as GLP-1 receptor agonists, antibiotics such asvancomycin (Van) or tobramycin, drugs for the treatment of malaria,anticancer agents, antifungal drugs, drugs for the treatment ofneurodegenerative diseases such as Alzheimer's disease and Parkinson'sdisease (e.g. dopamine agonists such as Levodopa), anti-viral drugs suchas interferon-a or ribavirin, or immunosuppressents (cyclosporine A orcyclosporine A derivatives), iron supplements, vitamin supplements, redcell production stimulators, anti-inflammatory biologies,anti-thrombolytics, statins, vasopressors and inotropic compounds.

A further object of the present invention relates to the use of theabove combinations for the prophylaxis and/or treatment of diseasescaused by a lack of hepcidin or iron metabolism disorders, such asparticularly iron overload states such as in particular thalassemia andhemochromatosis and other disorders as described in the presentapplication.

A further object of the present invention relates to the use of thecompounds as defined herein per se or the hereinabove describedcombination therapies, in combination with Blood transfusion.

The compounds, medicaments and or combined preparations according to thepresent invention may be administered orally, parentally, as well asintravenously.

For this purpose, the compounds according to the invention arepreferably provided in medicaments or pharmaceutical compositions in theform of pills, tablets, such as enteric-coated tablets, film tablets andlayer tablets, sustained release formulations for oral administration,depot formulations, dragees, granulates, emulsions, dispersions,microcapsules, microformulations, nanoformulations, liposomalformulations, capsules, such as enteric-coated capsules, powders,microcrystalline formulations, epipastics, drops, ampoules, solutions,suspensions, infusion solutions or injection solutions or in the form ofa preparation suitable for inhalation.

In a preferred embodiment of the invention the compounds areadministered in the form of a tablet or capsule, as defined above. Thesemay be present, for example, as acid resistant forms or with pHdependent coatings.

The compounds of the present invention as the active substance can beadministered, for example, with a unit dose of 0.001 mg/kg to 500 mg/kgbody weight, for example 1 to 4 times a day. However, the dose can beincreased or reduced depending on the age, weight, condition of thepatient, severity of the disease or type of administration.

Accordingly, a further object of the present invention relates tocompounds, medicaments, compositions and combined preparations asdefined above for the preparation of a medicament, particularly for theprophylaxis and treatment of any indication, state, disorder or diseaseas defined above, in particular for oral or parenteral administration.

A further object of the present invention relates to a method for theprophylaxis and treatment as defined above, such as in particular forthe prophylaxis and/or treatment of iron metabolism disorders beingassociated with or leading to increased iron levels and in particulariron overload, diseases related to or caused by increased iron levels oriron overload, iron storage diseases being associated with or leading toincreased iron levels, and diseases being associated with ineffectiveerythropoiesis, the method comprising administering, to a patient (humanor animal) in need thereof, a compound, a medicament, a composition or acombined preparation as defined above.

Therein, diseases being associated with, being related to, being causedby or leading to increased iron levels or iron overload are as definedabove.

A further object of the present invention relates to the use of thecompounds as defined above for the preparation of a medicament,particularly for the prophylaxis and treatment and of any indication,state, disorder or disease as defined above.

The compounds according to the invention of general structural formula(A-I) and (I) may basically be obtained by the processes described belowand as shown in the general procedures (General Schemes). Accordingly, afurther object of the invention is a process for the production of thecompounds of general formula (A-I) as described herein, which includes:

a) reacting compounds of formula (a)

with compounds of formula (b) NH—R¹R²,

to obtain compounds of formula (c)

and

b) further reacting said compounds (c) with compounds of formula (d)

with n=0 to 7, preferably 0 to 5, preferably 0 to 1 or 2, to obtaincompounds of formula (A-I);

wherein R¹, R², Z, A¹, R³ and Ar have the meaning as defined above. Inprinciple the order of reaction steps is optional. It is furtherpossible to start with the reaction of compounds (a) with compounds (d),followed by reaction with compound (b) to obtain compounds of formula(A-I). Further several intermediate steps are possible and severalintermediate compounds are obtained as shown in the following Examplesin detail. Several of the intermediate compounds are also novelcompounds, which shall be covered from the present invention.

A further object of the invention is a process for the production of thecompounds of general formula (I) as described herein, which includes:

a) reacting compounds of formula (a)

with compounds of formula (b) NH—R¹R²,

to obtain compounds of formula (c)

and

b) further reacting said compounds (c) with compounds of formula (d)

with n=0 to 7, preferably 0 to 5, preferably 0 to 1 or 2, to obtaincompounds of formula (I);

wherein X¹, Y¹, R¹, R², Z, A¹, R³ and Ar have the meaning as definedherein. In principle the order of reaction steps is optional. It isfurther possible to start with the reaction of compounds (a) withcompounds (d), followed by reaction with compound (b) to obtaincompounds of formula (I). Further several intermediate steps arepossible and several intermediate compounds are obtained as shown in thefollowing Examples in detail. Several of the intermediate compounds arealso novel compounds, which shall be covered from the present invention.

therein Rx indicates an optional substituent to X⁴ and corresponds to Y¹n indicates an integer as defined in context with A¹

therein Ar has the meaning as defined herein and may correspond to Het-2

therein Rx indicates an optional substituent R⁴ to Ar=Het-2 as definedherein

Ry=Ar has the meaning as defined herein and may correspond to Het-2

therein Y¹ indicates an optional substituent to X⁴ as defined hereinRx indicates an optional substituent to phenyl as defined hereinRy=Ar has the meaning as defined herein and may correspond to Het-2

Ry=Ar has the meaning as defined herein and may correspond to Het-2

therein Rx indicates an optional substituent to X¹ or X⁴ and correspondsto Y¹

Ry=Ar has the meaning as defined herein and may correspond to Het-2

Ry=Ar has the meaning as defined herein and may correspond to Het-2

Ry=Ar has the meaning as defined herein and may correspond to Het-2

Ry=Ar has the meaning as defined herein and may correspond to Het-2

Ar has the meaning as defined herein and may correspond to Het-2

Ry=Ar has the meaning as defined herein and may correspond to Het-2

Ar has the meaning as defined herein and may correspond to Het-2Rx=an optional substituent of phenyl as defined herein

Intermediates

Ry=substituent of phenyl as defined herein

EXAMPLES

The invention is illustrated in more detail by the following examples.The examples are merely explanatory, and the person skilled in the artcan extend the specific examples to further claimed compounds.

Pharmacological Assays

1. Hepcidin Internalization Assay (J774)

This cellular assay allows quantification of the binding of hepcidin toferroportin (Fpn) through microscopic detection of internalization of afluorescently labeled hepcidin into J774 cells. J774 is a mousemacrophage cell line which was shown to express Fpn endogenously uponincubation with iron (Knutson et al, 2005). Binding of hepcidin to Fpntriggers internalization and degradation of both hepcidin and Fpn.However, the TMR (6-carboxytetramethylrhodamine) fluorophore attached tohepcidin remains associated with the cell after degradation of thehepcidin peptide backbone. Therefore, microscopic detection ofcell-associated TMR fluorescence is a measure of hepcidin binding to Fpnand internalization of hepcidin and Fpn. If TMR-hepcidin is preventedfrom binding to Fpn, cellular TMR fluorescence remains low (Dürrenbergeret al, 2013). The effect of small molecular weight Fpn inhibitorcompounds in this assay was evaluated in vitro as described below.

J774 cells, harvested from ca. 80% confluent cultures, were plated at8×10⁵ cells/ml in complete medium (DMEM, 10% FBS, 1%Penicillin-Streptomycin) containing 200 μM Fe(III)NTA (nitrilotriaceticacid), 100 μl per well of 96 well MicroClear plates (Greiner; Cat.655090) and grown at 37° C. with 5% CO₂. After overnight incubation,cells were washed 3 times with pre-warmed DMEM w/o phenol red, 30μl/well of DMEM w/o phenol red was added after the final wash and 10μl/well of dilution series of test compounds were added in triplicates.J774 cells were pre-incubated with test compounds at 37° C. with 5% CO₂for 15 min. before TMR-hepcidin was added at 25 nM final concentration.Cells were incubated in a total volume of 50 μl at 37° C. with 5% CO₂for 2 hours, then Hoechst 33342 dye was added to a final concentrationof 0.5 μg/ml to stain nuclei and further incubated for 10 min. at 37° C.with 5% CO₂. Cells were washed 3 times with PBS and fixed in 100 μl of4% paraformaldehyde in PBS for 15 min. at room temperature. Afterremoval of the paraformaldehyde solution, cells were washed 3 times withPBS leaving 100 μl per well and the plates were sealed with foil plateseal. TMR (530-550 nm excitation/575-625 nm emission/400 ms exposuretime) and Hoechst 33342 (360-370 nm excitation/420-460 nm emission/10 msexposure time) fluorescence images were acquired using a ScanR plateimager (Olympus) with a 20× high NA objective. Four pictures wereacquired per well and fluorescence channel covering ca. 1500 cells perwell. The acquired image data was analysed with the ScanR image analysissoftware. Image analysis included detection of nuclei (Hoechst 33342fluorescence), identification of cell-associated regions, application ofa virtual channel and thresholding for rolling-ball-type backgroundreduction, followed by application of the Sum(Mean) algorithm to measurethe TMR fluorescence associated with cells as a quantitative measure forinternalized TMR-hepcidin. IC₅₀ values were calculated with theSum(Mean) raw data using “log(inhibitor) vs. response” curve fitting ofPrism 5 software (GraphPad Software Inc., version 5.02). For each dataset the fit of the “log(inhibitor) vs. response (three parameters)”model was compared to the fit of the “log(inhibitor) vs.response—Variable slope (four parameters)” model and the IC₅₀ data ofthe preferred model was used. IC₅₀ data of the Fpn inhibitors that weretested in the hepcidin internalization assay are listed in Table 1. TheIC₅₀ of unlabeled hepcidin in this assay is 0.015±0.011 μM.

Table 1 Average (AVE) IC₅₀ data of Fpn inhibitors tested in the hepcidininternalization assay is shown for multiple measurements

TABLE 1 Exp. Comp. No. J774 IC50 (uM) 1 0.012 2 0.035 3 0.17 4 0.155 50.063 7 0.4 8 0.24 12 0.08 16 0.90 19 10.0 21 6.7 35 0.19 36 0.25 370.81 38 0.03 39 0.07 40 0.049 42 0.60 43 0.25 44 1.33 45 0.44 46 0.59 470.72 49 30.58 54 0.46 55 0.015 56 0.41 57 0.10 58 0.01 59 0.05 60 2.3961 0.56 63 0.61 64 0.13 65 0.85 68 2.5 69 0.26 70 0.53 71 0.24 72 1.3674 0.21 75 0.53 76 0.34 77 0.35 79 0.037 80 0.345 81 0.42 82 0.006 830.096 84 0.40 85 0.029 86 0.48 87 0.19 88 0.78 89 0.089 90 0.025 91 2.0792 0.83 93 0.53 94 0.012 95 7.23 96 2.97 97 0.27 98 1.85 99 2.99 1000.46 101 0.28 102 0.058 103 2.37 104 0.90 105 0.077 106 1.52 108 0.13109 0.076 110 1.699 111 0.035 112 0.378 113 >25.0 (<50) 114 0.118115 >25.0 (<50) 116 1.000 117 9.695 118 0.103 119 0.164 120 0.034 1210.473 122 0.026 123 0.17 124 6.332 125 1.660 126 0.096 127 0.009 1280.005 129 0.353 131 0.090 132 0.580 134 0.377 135 3.407 136 >10.49(<50)  137 0.514 138 0.179 139 4.794 140 3.727 141 0.167 142 21.606 1440.012 145 0.385 148 2.085 151 0.111 152 0.004 154 0.0083 155 0.347 1562.462 157 0.717 158 0.047 159 0.091 160 0.256 161 0.361 162 0.297 1630.828 164 0.343 165 0.100 166 1.118 167 0.145 169 0.750 170 0.482 1710.026 173 0.006 174 0.141 175 1.025 176 0.957 177 4.203 178 3.637 1790.216 180 30.855 181 0.135 182 0.989 183 0.131 184 0.063 186 0.30 187 87188 1.16 189 0.060 191 0.33 192 13.56 193 0.287 194 0.72 195 0.21 1961.13 198 27.05 199 0.78 205 0.37 206 0.18 207 0.183 208 0.012 209 0.379210 4.913 211 0.747 212 8.514 214 14.1 215 27.7 218 4.5 219 2.43 2200.29 223 1.9 226 0.049 227 0.130 228 0.046 230 0.14 231 5.2 233 16 2360.15 239 0.036 242 8.92 243 0.032 244 0.090 247 0.082 249 0.040 2500.014 251 0.062 253 0.226 256 0.081 257 0.035 258 0.152 261 0.554 2650.070 273 0.228 274 0.145 275 26.035 276 27.160 277 0.011 278 0.476 2792.009 280 50.000

2. Biophysical Ferroportin-Hepcidin Binding Assay

This biophysical assay was developed to confirm inhibition of hepcidinbinding to ferroportin (Fpn) more directly. Incubation of TMR-hepcidinwith purified human Fpn isolated from Pichia pastoris yeast cellsexpressing human Fpn with a C-terminal FLAG affinity tag (Bonaccorsi diPatti, 2014) leads to increased fluorescence polarization (FP) of theTMR-hepcidin ligand. Small molecular weight Fpn inhibitors were testedfor inhibition of binding of TMR-hepcidin to Fpn, as detected bydose-dependent decrease of the TMR FP signal, as described in detailbelow.

A mixture of 1.3 μM human Fpn and 30 nM TMR-hepcidin in FP assay buffercontaining 50 mM Tris-HCl pH 7.3, 200 mM NaCl, 0.02% DDM, 0.1% BSA wasplated into a 384 well black low volume round bottom plate (Corning,Cat. 3677) at 16 μl per well. 8 μl of serial dilutions of test compoundswere added in duplicates to reach final Fpn and TMR-hepcidinconcentrations of 1 μM and 20 nM, respectively. Plates were incubatedfor 90 minutes at room temperature and parallel (S) and perpendicular(P) fluorescence was measured in a Synergy H1 fluorescence reader(BioTek). FP values were calculated in mP according to the followingformula.

${mP} = {\frac{F_{parallel} - F_{perpendicular}}{F_{parallel} + F_{perpendicular}} \times 1000}$

IC₅₀ values were determined with the calculated mP values as describedfor the hepcidin internalization assay and are listed in Table 2. TheIC₅₀ of unlabeled hepcidin in this assay is 0.37±0.067 μM.

Table 2 Average (AVE) IC₅₀ data of Fpn inhibitors tested in thebiophysical hepcidin-ferroportin binding assay is shown for multiplemeasurements.

TABLE 2 Exp. Comp. No. FP IC50 (uM) 1 0.016 2 0.017 3 0.071 5 0.0511 70.18 8 0.282 12 0.86 16 1.72 19 10.22 21 1.43 35 2.16 36 3.65 37 1.90 380.233 39 1.34 40 0.068 42 2.17 43 1.52 44 5.34 45 2.1 46 4.34 47 3.42 4923.97 54 11.37 55 0.087 56 0.566 57 0.43 58 0.076 59 0.270 60 0.974 611.690 63 0.846 64 1.237 65 0.95 68 4.056 69 1.513 70 1.065 71 0.508 720.931 74 0.451 75 1.830 76 5.083 77 2.813 79 0.820 80 2.276 81 2.974 820.374 83 1.046 84 2.412 85 1.866 86 4.957 87 2.249 88 6.757 89 0.922 900.418 91 12.060 92 1.268 93 1.03 94 0.044 95 13.040 96 7.286 97 2.132 985.713 99 4.327 100 1.419 101 0.315 102 0.258 103 2.525 104 1.756 1050.420 106 4.457 108 0.478 109 0.172 110 3.422 111 0.051 112 1.035 11371.2 114 0.23 115 109 116 0.058 117 9.0 118 0.25 119 5.3 120 0.071 1215.1 122 0.214 123 0.112 124 3.5 125 3.7 126 0.12 127 0.023 128 0.036 1291.078 131 0.133 132 0.57 134 0.97 135 36.90 136 6.85 137 1.04 138 0.16139 63.1 140 6.9 141 0.049 142 10.5 144 0.073 145 0.35 148 7.3 150 73151 0.089 152 0.023 153 57.77 154 0.030 155 0.46 156 0.71 157 4.27 1580.041 159 0.035 160 0.097 161 0.26 162 0.14 163 2.97 164 0.14 165 0.061166 0.37 167 0.104 169 0.54 170 0.28 171 0.066 173 0.031 174 0.32 1750.95 176 1.16 177 15.44 178 1.92 179 0.42 180 22.40 181 0.089 182 0.33183 0.19 184 0.10 186 0.14 187 35.48 188 0.63 189 0.047 191 0.52 19249.26 193 0.074 194 0.73 195 0.077 196 0.87 199 0.45 205 0.29 206 0.036207 0.047 208 0.019 209 0.038 210 1.877 211 0.154 212 3.758 214 3.188215 15.610 218 2.2 219 1.1 220 0.093 223 2.680 226 0.026 227 0.096 2280.021 230 0.058 231 1.658 233 6.776 236 0.123 239 0.038 242 27.810 2430.034 244 0.182 247 0.178 249 0.044 250 0.019 251 0.071 253 0.1481 2560.046 258 0.194 257 0.038 261 0.4396

3. Inhibition of Ferroportin Mediated Iron Export Activity in an IronResponse Assay

Intracellular iron levels are indirectly measured in this assay bymonitoring the activity of a beta-lactamase (BLA) reporter gene fused tothe human ferritin promoter and the associated iron regulatory element(IRE) contained within the 5′ untranslated region of the ferritin mRNA.Expression of ferroportin (Fpn) in such a cell line leads to iron effluxand lower iron levels as reflected by lower activity of the reportergene. On the other hand, inhibition of Fpn-mediated iron efflux resultsin elevated cellular iron levels which is detected as increased reportergene activity. Small molecular weight Fpn inhibitor compounds weretested for dose-dependent effects in this in vitro iron response assayas described below.

The HEK-293 cell line #354 was generated by stable integration of (i) ahuman Fpn-GFP fusion construct inserted in a derivative of thedoxycycline-inducible pTRE-Tight-BI plasmid (Clontech, Cat. 631068) and(ii) a human ferritin promoter-BLA reporter gene into a derivative ofthe HEK-293 Tet-ON Advanced cell line (Clontech). To generate theferritin-BLA reporter gene construct, a 1.4 kb fragment of the humanferritin H promoter was amplified by PCR from human genomic DNA (forwardprimer 5′-CAGGTTTGTGAGCATCCTGAA-3′; reverse primer5′-GGCGGCGACTAAGGAGAGG-3′) and inserted in front of the BLA gene presentin the pcDNA™6.2/cGeneBLAzer™-DEST plasmid (Invitrogen, Cat. 12578-043)thereby replacing the original CMV promoter and placing the IRE thatregulates translation of the ferritin gene ca. 170 bp upstream of thestart codon of the reporter gene. #354 cells were harvested from ca. 80%confluent cultures, seeded at 1.8×10⁵ cells/ml in DMEM/F12 GlutaMAX™medium (Invitrogen, Cat. 31331-028) containing 10% FBS (Clontech, Cat.631106), 1% Penicillin-Streptomycin, 200 μg/ml Hygromycin B (Invitrogen,Cat. 10687-010), Blasticidin 5 μg/ml, (Invitrogen, Cat. R210-01), 4μg/ml doxycycline (Clontech, Cat. 631311), 50 μl per well of 384 wellPDL-coated plates and grown at 37° C. with 5% CO₂. After overnightincubation, 10 μl/well of dilution series of the test compounds wereadded in quadruplicates and plates were further incubated overnight at37° C. with 5% CO₂. Cells were washed 3 times with HBSS leaving 25 μlper well. BLA activity was detected by adding 5 μl/well of theGeneBlazer reagent CCF4-AM (Invitrogen, Cat. K1085) to the cells. Afterincubation of the plates in the dark at 18° C. for 60 min., blue andgreen fluorescence signals were measured in a Safire2 fluorescence platereader (Tecan) with excitation at 410 nm and emissions at 458 nm (blue)and 522 nm (green). The ratio of blue/green fluorescence as a measurefor BLA activity was calculated and EC₅₀ values were determined with thecalculated blue/green fluorescence ratios as described for the hepcidininternalization assay. The EC₅₀ data of the tested Fpn inhibitors islisted in Table 3. The EC₅₀ of hepcidin in this assay is 0.096±0.063 μM(n=37).

Table 3 Average (AVE) EC₅₀ data of Fpn inhibitors tested in the ironresponse assay is shown for multiple measurements.

TABLE 3 Exp. Comp. No. BLAzer EC50 (uM) 1 0.93 2 1.03 3 3.17 4 1.259 50.734 7 12.9 8 10.1 12 8.27 37 7.92 38 2.98 39 2.90 40 1.45 42 36.26 4330.95 44 18.31 46 38.67 55 1.23 56 10.38 57 2.11 58 1.72 59 1.38 6137.46 64 4.53 65 32.33 68 10.40 71 1.79 75 6.00 79 0.84 82 0.76 84 13.1585 18.69 86 22.34 87 16.56 88 13.08 89 5.05 90 4.03 92 17.78 93 20.55 940.53 97 1.81 99 22.80 100 6.56 101 2.92 102 1.85 105 2.63 108 4.12 1092.62 111 0.62 112 13.47 114 4.45 116 2.79 118 2.69 120 1.60 122 4.33 1233.04 126 1.26 127 0.42 128 0.097 129 10.56 131 0.75 132 13.94 134 4.09135 >20.00 <50 136 >20.00 <50 137 5.75 138 1.72 139 >20.00 <50140 >20.00 <50 141 1.11 144 0.47 145 4.7 151 0.72 152 0.17 154 0.74 1558.17 156 16.13 158 0.62 159 1.16 160 1.91 161 17.18 162 4.37 164 2.11165 2.59 167 2.84 169 8.23 170 3.96 171 1.23 173 0.10 174 7.73 179 25.94181 3.72 182 6.84 183 3.58 184 1.60 186 4.94 188 >39.07 <50 189 3.10 1918.38 193 3.64 194 >3.22 <50 195 3.55 196 12.72 199 5.70 205 3.83 2063.26 207 2.76 208 0.50 209 3.38 211 6.1 220 17.0 226 2.34 227 24.90 2282.12 230 6.38 236 12.72 239 0.88 243 1.40 244 3.86 247 3.15 249 1.55 2500.46 251 2.27 253 3.176 256 0.628 257 0.636 258 2.525 265 1.998 2733.604 274 1.122 277 0.17

4. Ferroportin Internalization and Degradation Assay

HEK-293 cell line #354 (described in example 3) was used to measure thecapacity of the compounds to induce internalization and degradation offerroportin (Fpn) by fluorescence activated cell sorting (FACS). GrowingHEK-293 #354 cells in doxycycline containing media induced expression ofhuman Fpn-GFP fusion protein on the cell surface. Data from 10independent experiments showed that cultivation of HEK#354 cells for 48h in the presence of 4 μg/ml doxycycline induced in average 42.6%±6.4%Fpn-GFP-positive cells. Small molecular weight Fpn inhibitor compoundswere tested for dose-dependent effects on the Fpn-GFP mean fluorescenceintensity (MFI) on HEK-293 cell line #354, as described below.

HEK#354 cells were harvested from ca. 80% confluent cultures, seeded at0.6×10⁶ cells/ml in DMEM/F12 GlutaMAX™ medium (Invitrogen, Cat.31331-028) containing 10% FBS (Clontech, Cat. 631106), 1%Penicillin-Streptomycin (Invitrogen, Cat. 15140-122), 200 μg/mlHygromycin B (Invitrogen, Cat. 10687-010), Blasticidin 5 μg/ml,(Invitrogen, Cat. R210-01), 4 μg/ml doxycycline (Clontech, Cat. 631311),50 μl per well of 384 well plates (Greiner; Cat. 781091) and grown at37° C. with 5% CO₂. After overnight incubation, 10 μl/well of dilutionseries of the test compounds were added in quadruplicates and plateswere further incubated overnight at 37° C. with 5% CO₂. Cells werewashed once with FACS buffer (PBS containing 1% FBS, 2 mM EDTA and 0.05%NaN₃), harvested in FACS buffer with 0.5 μg/ml propidium iodide (Sigma,Cat. P4864) and analyzed in a flow cytometer (CANTO™ II, BD Biosciences)equipped with high throughput sampler. Live HEK#354 cells were gated aspropidium iodide negative population and analyzed for expression ofFpn-GFP. MFI of Fpn-GFP of >2000 live cells for each compound dilutionwas calculated using FlowJo (Tree Star's, Oregon) and the potency of theFpn-inhibitors to induce internalization and degradation of Fpn-GFP wascalculated as described for the hepcidin internalization assay. EC₅₀data of the Fpn inhibitors that were tested in the ferroportininternalization and degradation assay by FACS are listed in Table 4. Theaverage EC₅₀ value of hepcidin in this assay is 0.004±0.002 μM.

Table 4 Average (AVE) EC₅₀ data of Fpn inhibitors tested in theferroportin internalization and degradation assay is shown for multiplemeasurements.

TABLE 4 Exp. Comp. No. EC50 (uM)  1 0.22  2 0.63  3 1.84  4 1.198  50.549  7 1.89  8 1.13  40 0.81  55 1.029  58 0.387  82 0.689  94 0.22109 0.885 111 0.075 112 3.775 113 41.330 114 2.956 115 38.250 116 0.590117 >25.0 <50 118 4.908 120 0.530 122 3.015 123 4.507 126 0.757 1270.081 128 0.006 129 4.464 131 0.194 132 2.148 134 5.194 135 21.210 13617.860 137 11.073 138 0.678 139 >20.0 <50 140 >20.0 <50 141 0.290 14239.745 144 0.043 145 1.245 148 1.050 151 0.523 152 0.071 154 0.130 1553.954 156 12.110 157 7.862 158 0.325 159 0.757 160 1.287 161 5.300 1621.412 163 7.411 164 3.207 165 0.587 166 >20.0 <50 167 1.462 169 4.121171 0.571  171-B 0.319 173 0.071 174 3.960 175 12.452 176 16.985 1791.207 181 0.930 182 23.692 183 1.850 184 1.188 186 5.059 188 35.985 1890.679 191 2.512 193 3.946  193-B 1.391 194 8.050 195 1.459 196 24.845199 2.966 205 11.115 206 2.072 207 1.608 208 0.15 209 2.440 211 4.43 213× 3 HCl 4.14 220 3.82 226 0.49 227 1.58 228 0.46  228-B 0.22 230 0.95231 8.33 236 2.16 239 0.32 243 0.51 244 1.69 247 2.18 249 0.95 250 0.60251 1.42 253 1.828 256 0.736 257 0.518 258 1.231 265 1.196 273 1.721 2740.582 277 0.069

5. Ferroportin Ubiquitination and Degradation

Exposure of cells expressing ferroportin (Fpn) to hepcidin is known totrigger ubiquitination and subsequent internalization and degradation ofFpn (Qiao, 2012). The potential of Fpn inhibitors to induce Fpnubiquitination and degradation was investigated with animmunoprecipitation assay using the J774 mouse macrophage cell linewhich expresses Fpn upon treatment with iron.

J774 cells (DSMZ, Cat. ACC170) were seeded at 0.8×106 cells/ml in 15 mlof medium (DMEM Gibco Cat. 11971-025, 10% heat inactivated FBS GibcoCat. 10500-064, 1% Penicillin-Streptomycin Gibco Cat. 15140-122)containing 200 μM Fe(III)-NTA into 10 cm tissue culture dishes (GreinerCat. 664160) and grown overnight at 37° C. with 5% CO₂. Cells wereincubated with synthetic human hepcidin (Bachem, Cat. H-5926) or Fpninhibitor compounds for 10 min or 120 min. Cells were washed and lysedwith ice-cold lysis buffer (Pierce, Life Technoligies, Cat. 87787)including 1×HALT protease inhibitor cocktail (Life technologies, Cat.78429) and 10 mM iodoacetamide (Sigma, Cat. 16125) to stabilizeubiquitinated proteins. Immunoprecipitation was done using the PierceClassic IP Kit (Life Technologies, Cat. 26146) following themanufacturer's protocol. Briefly, 2 mg protein in 1.25 ml IP lysisbuffer was incubated by mixing for 1 h at 4° C. with control agarosebeads to pre-clear the lysate and reduce nonspecific signal. Unboundlysate was then incubated overnight with 12 μg per reaction of theaffinity purified anti-Fpn antibody F308 that was raised against a GSTfusion protein of mouse Fpn amino acids 224-308. Immune complexes werecaptured by pipetting 141 μl settled Pierce Protein A/G Plus Agarosebeads (Life Technologies, Cat. 20423) per reaction and the slurry wasincubated for 1.5 h at 4° C. with gentle end-over-end mixing. The beadswere washed and immune complexes were eluted directly with 75 μl SDSNuPAGE LDS sample buffer (Life Technologies, Cat. NP0007) containing DTT(Life Technologies, Cat. NP0009).

After immunoprecipitation samples were analyzed by Western blottingusing a rabbit anti-mouse MTP1 antiserum (Alpha DiagnosticInternational, Cat. MTP11-A) and a mouse anti-mono- andpolyubiquitinylated conjugates monoclonal antibody (Enzo Lifesciences,Cat. BML-PW8810) for detection of ferroportin and ubiquitin,respectively. Mouse monoclonal anti-rabbit IgG light chain (Abcam, Cat.ab99697) and anti-mouse IgG H&L (Abcam, Cat. ab6789) HRP conjugates wereused as secondary antibodies.

A selection of eleven Fpn inhibitors were tested in this assay andcompared to hepcidin. As shown in FIG. 1 and Table 5, treatment of cellswith Fpn inhibitors lead to rapid ubiquitination within 10 minutes (FIG.1 upper panel) and degradation after 2 hours of Fpn (FIG. 1 lowerpanel). The degree of Fpn degradation by the Fpn inhibitors wascomparable to the effect of hepcidin. However, hepcidin treatmentresulted in ubiquitinated Fpn with higher molecular weight compared toFpn inhibitor treatment, suggesting poly-ubiquitination versusmono-ubiquitination by hepcidin versus Fpn inhibitors, respectively.

Table 5 Summary of Fpn inhibitors tested in the Fpn ubiquitination anddegradation assay. The effects of treatment with Fpn inhibitors on Fpndegradation and Fpn ubiquitination were scored by visual inspection ofWestern blots (+ comparable to hepcidin; − no effect; +/− intermediateeffect).

TABLE 5 Exp. Comp. Concentration Fpn Ubiquitination Fpn Degradation No.(uM) (10 min.) (120 min.) 1 0.12 + + 40 1.9 + + 94 0.3 + + 111 0.3 + +126 0.8 +/− + 127 0.1 + + 128 0.05 + + 152 0.04 + +/− 167 1.5 + + 2080.2 + + 226 0.5 + + hepcidin 0.15 + +

FIG. 1 Fpn inhibitor trigger ubiquitination and degradation of Fpnexpressed in a mouse macrophage cell line. J774 cells were incubatedovernight with Fe(III)-NTA to induce expression of Fpn. Cells were thentreated with ca. 10-fold IC₅₀ concentrations, as determined in thehepcidin internalization assay (see Table 1), of hepcidin (Hepcidin, 150nM) or Fpn inhibitors Example Compound No. 208 (210 nM), ExampleCompound No. 167 (1.5 μM), Example Compound No. 127 (120 nM), ExampleCompound No. 152 (40 nM) for 10 or 120 min before harvesting andimmunoprecipitation with the anti-Fpn antibody F308. Mock treated cellswere harvested after 120 min (Control).

Immunoblotting of immunoprecipitates with the anti-Fpn antibody MTP1revealed disappearance of ferroportin 120 min after treatment with theFpn inhibitors, to a similar extent as in the sample treated withhepcidin (upper panel). Rapid ubiquitination of Fpn was observed 10 minafter treatment of cells with Fpn inhibitors and hepcidin. Proteinmolecular weight standards are indicated on the left in kD.

6. Inhibition of Iron Efflux by Ferroportin Inhibitors

The activity of hepcidin and ferroportin inhibitor compounds regardingtheir ability to block iron export via ferroportin was tested on T47Dcells (ECACC, Cat. 85102201) as described below.

Cells were plated in 24-well plates (Greiner, Cat. 662160) containing350′000 cells/well and incubated overnight with 100 μM ⁵⁸Fe(⁵⁸Fe(II)-Sulfate, Vifor Pharma Batch No. ROR 3085) in 500 μM L-AscorbicAcid (Sigma Aldrich, Cat. 795437) containing growth medium. Cells werewashed once with 500 μl iron uptake buffer (IUB; PIPES 40 mM, Cat.P1851, Glucose Monohydrate 10 mM, Cat. 49158, Sodium Chloride 260 mM,Cat. 71379, Potassium Chloride 20 mM, Cat. P9541, Magnesium Sulfate 2mM, Cat. 63138, Sigma Aldrich), then once with removal buffer (2 minincubation, BPDS 100 μM, Cat. 11890 and Na₂S₂O₄ 500 μM, Cat. 157953,Sigma Aldrich, in IUB) and again twice with IUB. A serial dilution ofhepdicin (Bachem) or ferroportin inhibitors (4 μM-0.0064 μM, 5 folddilution) was added in a total volume of 0.6 ml per well. Cells wereincubated at 37° C. with 5% CO2 for 20 h. Supernatants were collectedand ⁵⁸Fe was measured using inductively coupled plasma mass spectrometry(ICP-MS, Thermo Scientific, Element 2). Pellets were harvested forprotein concentration measurements. Results are plotted as ng ⁵⁸Fe insupernatant per mg protein in cell lysates. Example Compound No. 127inhibited iron efflux with similar potency as the endogenous Fpn ligandhepcidin (FIG. 2).

FIG. 2 Representative iron efflux inhibition of Hepcidin (IC₅₀: 0.086μM) and Example Compound No. 127 (IC₅₀: 0.080 μM).

7. Hypoferremia in Naïve Mice

Injection of synthetic hepcidin in wild-type (WT) naïve mice resulted ina reduction of serum iron levels (40-50% from the vehicle control) witha maximal effect at 3-4 hours post treatment (Rivera, 2005; FIG. 3A).This data suggested that the injected hepcidin binds to and triggers theinternalization of ferroportin (Fpn) on duodenal enterocytes andsplenocytes, causing a rapid drop in serum iron. Similarly, orallyadministered small molecular weight Fpn inhibitors decreased the levelsof serum iron of WT C57BL/6 mice in a dose-dependent manner (FIG. 3B)with an efficacy comparable to hepcidin. This data validated the use ofWT mice as a simple and reliable model for testing the acute efficacy ofFpn inhibitors in vivo.

Female C57BL/6 mice (Janvier, France) at age of 9 weeks were fed astandard diet (Harlan Provimi Kliba 3436) and treated per os (p.o.) withcompounds or the corresponding amount of vehicle at a volume of 10 ml/kgbody weight. Fpn inhibitors were formulated in 0.5%methylcellulose/water or 20% cremophor EL/water and dosed p.o. in miceat 10, 30 or 100 mg/kg body weight. Three hours later, mice werepre-terminally anesthetized in isoflurane chambers and blood wascollected by retro-orbital bleeding. Mice were sacrificed by cervicaldislocation and spleens, livers and duodena were harvested and used forbiomarker analysis. All experiments have been conducted in compliancewith the license approved by the responsible veterinarian authorities.Serum was isolated by centrifugation of blood into gel-containingmicrotainers and serum iron was determined by the MULTIGENT Iron assay(Abbott Diagnostics, 6K95). Eight mice per group were used and one-wayANOVA with Bonferroni's multiple comparison test was performed toanalyze the statistical differences between the experimental groups. Theefficacy of selected Fpn inhibitors in WT C57BL/6 mice is shown in Table6.

FIG. 3 Serum iron reduction induced by hepcidin and ferroportininhibitor according to Example Compound 94 (Example Compound No. 94).

A Kinetic of serum iron in naïve C57BL/6 mice injected with synthetichepcidin (5 mg/kg) intraperitoneally (i.p.) for the indicated time.*-***—indicate statistically significant serum iron reduction comparedto PBS-treated mice.

B Serum iron levels in naïve C57BL/6 mice treated with the indicatedamounts of either hepcidin (i.p.) or Example Compound 94 (ExampleCompound No. 94). (p.o.) for 3 h.

Table 6 Efficacy of Fpn inhibitors tested in the naïve mousehypoferremia model.

Serum iron reduction induced by selected ferroportin inhibitors dosedp.o. in naïve WT C57BL/6 mice at 10, 30 and 100 mg/kg. Relative serumiron reduction at 3 h after dosing was calculated by subtracting theaverage of serum iron values of animals dosed with the Fpn inhibitorfrom that of vehicle-treated animals. The difference in average serumiron values between vehicle and compound treated groups was then dividedby the average of serum iron of the vehicle control group and listed aspercentage.

TABLE 6 Serum Iron Reduction at 3 h (%) Exp. Comp. Dose Dose Dose No. 10mg/kg 30 mg/kg 100 mg/kg 1 0 28 51 2 9 26 50 12 15 20 45 39 10 20 35 4010 30 50 55 0 20 55 58 20 30 40 90 0 0 40 94 30 50 80 118 8 24 49 126 723 62 127 17 47 54 137 −2 14 25 154 13 35 56 159 4 26 60 167 19 17 34171 10 42 61 193 13 11 31 208 50 65 73 228 13 26 55 239 12 20 51 250 518 40 277 6 21 54

8. Prevention of Iron Absorption in Anemic Rats

To assess the in vivo efficacy of ferroportin (Fpn) inhibitors to blockiron absorption, a series of Fpn inhibitors were tested in an anemic ratmodel for iron absorption. Wistar rats (3-4 weeks old, n=5, JanvierLabs) were fed a low iron diet (Provimi-Kliba, Cat. 2039) until theirhemoglobin (Hb) values reach 7-8 g/dl one day before dosing of the Fpninhibitor compounds. One hour before oral application of 0.5 mg/kg offerrous sulfate, test compounds formulated in methyl cellulose orCremophor were dosed orally. Blood samples were taken by tail veinpuncture one hour before administration of iron (−1 h), immediatelyafter dosing of the Fpn inhibitors (0 h) and one hour (1 h), three hours(3 h) and occasionally up to 6 hours (6 h) after dosing of the testcompounds. Serum iron levels were measured (Abbott Diagnostics, Cat.6K95) and inhibition of the rise of serum iron three hours after dosingof the test compound was calculated as a measure for efficacy of the Fpninhibitors in blocking iron absorption (Table 7). As shown in FIG. 4,oral administration of the Fpn inhibitor Example Compound No. 55 at 3mg/kg, 10 mg/kg or 30 mg/kg reduced serum iron levels by 54%, 72% and89%, respectively, three hours after iron dosing when compared to serumiron levels of vehicle-control animals before iron dosing and correctedfor the baseline serum iron levels in vehicle-treated animals that didnot receive a dose of iron.

Table 7 Fpn inhibitors tested in the anemic rat model for inhibition ofiron absorption. Relative inhibition values (%) of serum iron levels areshown, corrected for average baseline serum iron levels of the controlgroup which did not receive a dose of oral iron, compared to controlgroups treated with vehicle before iron dosing. Average values of groups(n=5) treated with the indicated doses of Fpn inhibitor are shown.Statistically significant (2-way ANOVA with Bonferroni post test)differences observed between compound-treated and vehicle-treated groupsare indicated (*** p<0.001; ** p<0.01, * p<0.05).

FIG. 4 Dose-dependent block of iron absorption in anemic rats by Fpninhibitor Example Compound No. 55. One hour before oral administrationof a dose of ferrous sulfate (0.5 mg/kg), Example Compound No. 55 wasorally administered either at 3 mg/kg (light blue line), 10 mg/kg (greenline) or 30 mg/kg (dark blue line). Dosing of Example Compound No. 55led to statistically significant (p<0.001) and dose-dependent inhibitionof the increase in serum iron observed 3 hours after iron dosing inanimals treated with vehicle (red line). Baseline serum iron levels inthe vehicle-treated group that did not receive a dose of iron are alsoshown (black line). Averages with standard deviations are plotted foreach treatment group and time point.

TABLE 7 Serum Iron Inhibition (%) at 3 h Exp. Comp. Dose Dose Dose DoseDose No. 1 mg/kg 3 mg/kg 10 mg/kg 30 mg/kg 100 mg/kg 1 nd 2.1   42.6**  64.9*** nd 2 nd −3    29**  57*** nd 40 nd nd 32**  53*** 97*** 55 nd54*** 72*** 91*** 109***  58 nd nd nd 64*** 95*** 94 59*** 0  70*** ndnd 127 nd −8    47*** 79*** nd 154 nd 22*  16   58*** nd 159 nd 21** 32*** 71*** nd 167 nd −39***   −34***   47*** nd 171 nd −3    16** 34*** nd 208 nd 59*** 86*** 109***  nd

9. Correction of Hyperferremia in Beta2-Microglobulin Deficient Mice

Mutations in genes involved in sensing the systemic iron stores, such ashepcidin (Hamp1), hemochromatosis protein (HFE), hemojuvelin (HJV) andtransferrin receptor 2 (TFR2) cause iron overload in mice and men. HFE,HJV and TFR2 molecules on hepatocytes are necessary for signaling ofappropriate hepcidin production and their deficiency results inpathophysiologically low hepcidin levels and excessive iron absorption.HFE mutations is the most frequent cause of hereditary hemochromatosis(HH) in Caucasian adults. HFE is a MHC class I-like membrane moleculethat associates with beta 2-microglobulin and participates in hepcidintranscriptional regulation through the bone morphogenetic proteinreceptor (BMPR) pathway. HFE−/− mice have decreased hepcidin levels,develop hyperferremia and high hepatic iron levels, which makes them asuitable animal model for studying iron overload in humans (Zhou, 1998).Mice deficient in beta 2-microglobulin (b2m−/−) develop hyperferremiaand hemochromatosis similarly to HFE−/− animals, as beta 2-microglobulinis necessary for the cell-surface expression and function of HFE(Rothenberg and Voland, 1996). Due to the unavailability of HFE−/− mice,b2m−/− mice were used as a model of iron overload. A pilot studyconfirmed that HFE−/− and b2m−/− mice have similar ironmetabolism-related parameters.

Female and male homozygous b2m−/− mice were supplied from JacksonLaboratories (B6.129P2-B2mtm1Unc/J, Stock Number: 002087) at age of 6 to7 weeks and fed standard diet (Harlan Provimi Kliba 3436) ad libitum.Age and gender matched WT C57BL/6 mice are supplied by Charles River. Tostudy the acute effects of ferroportin (Fpn) inhibitors in iron overloadb2m−/− mice were treated with compounds or the corresponding amount ofvehicle at a volume of 10 ml/kg body weight. Fpn inhibitor compoundswere formulated in 0.5% methylcellulose/water or 20% cremophor EL/waterand dosed p.o. in mice at 50 mg/kg body weight. WT controls receivedonly vehicle. Three hours later, mice were pre-terminally anesthetizedin isoflurane chambers and blood was collected by retro-orbitalbleeding. Mice were sacrificed by cervical dislocation and spleens,livers and duodena were harvested and used for biomarker analysis. Allexperiments have been performed in compliance with license approved bythe responsible veterinarian authorities. Serum was isolated bycentrifugation of blood into gel-containing microtainers (BDBiosciences) and serum iron was determined by the MULTIGENT Iron assay(Abbott Diagnostics, Cat. 6K95). Four to nine mice per group were usedand one-way ANOVA with Bonferroni's multiple comparison test was appliedto analyze the statistical differences between the experimental groups.

To investigate the effects of Fpn inhibitors Example Compound No. 40 andExample Compound No. 94 in conditions of iron overload b2m−/− mice or WTcontrols were dosed with Fpn inhibitors or vehicle for 3 h. Due to theirgenetic deficiency, b2m−/− mice treated with vehicle showedsignificantly higher serum iron levels compared to WT mice (FIG. 5,group average of 60 μM in A and 56 μM in B). Treatment of b2m−/− micewith Example Compound No. 40 or Example Compound No. 94 at 50 mg/kg for3 h corrected the elevated serum iron to the levels observed in WTcontrols. These data demonstrated the acute efficacy of small molecularweight ferroportin inhibitors in a disease relevant model. Serum ironcorrection was observed in further studies as summarized in Table 8.

FIG. 5 Complete correction of the elevated serum iron levels in b2m−/−mice by treatment with the ferroportin inhibitors Example Compound No.40/methylcellulose (A.) and Example Compound No. 94/cremophor EL (B.)for 3 h.

Table 8 Fpn inhibitors tested in the beta2-microglobulin deficient mousemodel for lowering elevated serum iron levels Blood was collected 1 (#)or 3 (##) hours after oral administration of the indicated doses of Fpninhibitors to beta2-microglobulin deficient mice and serum ironconcentrations were measured.

Relative reduction (%) of serum iron levels are shown, which werecalculated by subtracting the average of serum iron values of animalsdosed with the Fpn inhibitor from that of vehicle-treated animals. Thedifference in average serum iron values between vehicle and compoundtreated groups was then divided by the average of serum iron of thevehicle control group and listed as percentage. Values are listedseparately for female (?) and male (o) animals, because a markedsex-dependent difference in efficacy was noted. Statisticallysignificant (2-way ANOVA with Bonferroni post test) differences observedbetween compound-treated and vehicle-treated groups are indicated (***p<0.001; ** p<0.01, * p<0.05).

TABLE 8 Serum Iron Reduction (%) Exp. Comp. Dose Dose No. 20 mg/kg 60mg/kg  1 ♀  31** 52** ♂  31** 59**  2 ♀ 27 57** ♂ 29 66**  40^(#) ♀  013  ♂  35** 32**  40^(#) ♀ nd 10  ♂ nd 58**  94^(##) ♀ nd 47  ♂ nd 67 127 ♀   47***  74*** ♂ 21 83** 208^(##) ♀  9  49*** ♂ 44 67**

10. Prevention of Iron Overload in Beta2-Microglobulin Deficient Mice

As a result of decreased hepcidin levels and increased iron absorptionin the gut beta2-microglobulin deficient (b2m−/−) mice on a standarddiet accumulate excessive amounts of iron in liver, heart and pancreas.A pilot study showed that liver iron loading in b2m−/− starts at age of3-4 weeks and that liver iron levels reaches up to 4 fold the liver ironcontent of wild-type (WT) mice at age of 6 weeks. In addition, feeding 3week old b2m−/− mice a diet with low iron content (LID) immediatelyafter weaning prevented liver iron loading by age of 6-7 weeks. Theefficacy of the Fpn inhibitors to prevent liver iron accumulation inb2m−/− mice was investigated. Three weeks old b2−/− mice fed LID weredosed with either Fpn inhibitor or vehicle (methylcellulose; 10 ml/kg).Mice had access to drinking water supplemented with 1 mM⁵⁸Fe(II)-sulfate and 10 mM ascorbic acid. Dosing of Fpn inhibitor orvehicle followed by exposure to iron-containing water was repeated for14 days. Mice are euthanized and the liver and spleen iron contents wereanalyzed by ICP-OES (all iron isotopes) and liver tissue is alsoanalyzed for ⁵⁸Fe concentration (ICP-MS). The data summarized in Table 9illustrates that oral dosing of Fpn inhibitors for two weeks preventedliver iron loading in b2m−/− mice and increased spleen ironconcentrations, indicating inhibition of ferroportin both in theintestine and in the spleen.

These data demonstrated the efficacy of a small molecular weightferroportin inhibitor to prevent liver iron loading in b2−/− mice, whichprovides a proof of concept in a disease-relevant model.

Table 9 Fpn inhibitors tested in the beta2-microglobulin deficient mousemodel for inhibition of liver iron overload.

Livers and spleens were collected after 14 day treatment (p.o.; b.i.d)of beta2-microglobulin deficient mice with the indicated doses of Fpninhibitors. Total liver and spleen tissue iron concentrations weremeasured using ICP-OES and ⁵⁸Fe liver concentrations were determinedwith ICP-MS. Relative changes (%) of tissue iron levels are shown, whichwere calculated by normalizing the difference between the averages oftissue iron values of animals dosed with the Fpn inhibitors and those ofvehicle-treated animals with the average of vehicle controls. Values arelisted separately for female (♀) and male (♂) animals, because a markedsex-dependent difference in efficacy was noted. Statisticallysignificant (2-way ANOVA with Bonferroni post test) differences observedbetween compound-treated and vehicle-treated groups are indicated (***p<0.001; ** p<0.01, * p<0.05). nd, not determined; na, not available.

TABLE 9 Total Spleen Total Liver ⁵⁸Fe Liver Iron Increase (%) IronReduction (%) Iron Reduction (%) Dose (mg/kg) Exp. Comp. No. 20 60 20 6020 60 1 ♀ 21 65 −1 15  4 59 ♂ 28 49 16 25 −8 22 2 ♀ 13  1 26 45  60**  77*** ♂ 18 −20  10 28 24 70 40 ♀  50*   85*** 32  67* 44  80* ♂ 25 2431   69***  53*   81*** 40 ♀ nd  9 nd 66 nd 67 ♂ nd 36 nd  85** nd  95**94 ♀ nd 65 nd 57 nd na ♂ nd 41 nd 79 nd na 127 ♀  71* 51 −38   2 34  63*** ♂ −7 −16   50**   65***   71***   73*** 208 ♀  56**  150*** 15 8  71*  87** ♂ 21 43 41  84** 58  94**

11. Improvement of Anemia, Ineffective Erythropoiesis and Iron Overloadin a Mouse Model of β-Thalassemia Intermedia

β-thalassemia is inherited anemia caused by mutations in the β-globingene of hemoglobin resulting in abnormal red blood cells with decreasedlife span. The most severe form, thalassemia major, requires bloodtransfusions which result in secondary iron overload. Patients withthalassemia intermedia have a moderate transfusion-independent anemiabut still develop iron overload due to inefficient erythropoiesis andchronic repression of hepcidin production.

As shown in the previous examples, oral ferroportin (Fpn) inhibitorssimilarly to hepcidin blocked ferroportin mediated export of iron fromcells in vitro and upon dosing in wild-type mice transiently reducedserum iron. Based on these findings and published studies (Schmidt P J,et al, Blood 2013, Guo S, et al, JCI, 2013 and Casu C. et al, Blood,2016) Fpn inhibitors were examined with respect to its capacity toprevent iron loading and improve erythropoiesis in thalassemiaintermedia by restricting iron absorption and reutilization fromsenescent erythrocytes. The efficacy of Fpn inhibitors was investigatedusing a mouse model of transfusion-independent β-thalassemia. Mice withheterozygous deletion of β1 and β2 globin genes (called Hbb th3/+ mice)develop transfusion-independent anemia, ineffective erythropoiesis,splenomegaly and secondary iron overload in spleen, liver and kidneys.Heterozygous Hbb th3/+ mice were supplied from Jackson Laboratories (B6;129P-Hbb-b1tm1Unc Hbb-b2tm1Unc/J, Stock Number: 002683) at age of 8-18weeks and during experiments fed a low iron diet (Harlan Provimi Kliba2039, 13.4 ppm Fe) ad libitum. Hbb th3/+ mice were dosed twice dailywith either compound at 20 or 60 mg/kg or with methylcellulose (10ml/kg, Sigma, Cat. 274429) as a vehicle. Between both doses mice hadaccess to drinking water supplemented with 1 mM ⁵⁸Fe(II)-sulfate (ViforPharma, Batch No. ROR 3096) and 10 mM ascorbic acid (Sigma, Cat. 795437)for 6 h. The concentration of ⁵⁸Fe(II)-Sulfate supplied in the drinkingwater has been adjusted to substitute for intake of standard rodent dietwith iron content of 250 ppm. Water without ⁵⁸Fe(II)-Sulfate andascorbic acid was provided during the remaining 18 h. Dosing of Fpninhibitors or vehicle followed by exposure to iron-containing water wasrepeated for 20 to 46 days in individual experiments.

As previously shown in wild-type and b2m−/− mice, Fpn inhibitors dosedfor 3 h in Hbb th3/+ mice reduced efficiently serum iron levels also inthis mouse strain (Table 10), demonstrating the ability of these smallmolecules to cause iron restriction.

Hbb th3/+ mice are anemic with hemoglobin levels in the range of 70-80g/L. Oral administration of Fpn inhibitors in Hbb th3/+ mice for twoweeks increased significantly hemoglobin levels compared to vehicletreated mice (Table 10). The change of hemoglobin levels incompound-dosed compared to vehicle-treated group reached 19-22 g/L bythe study end. Additional hematologic parameters were measured interminal blood using automated blood cell analyzer. Treating Hbb th3/+mice with Fpn inhibitors increased red blood cell counts, hematocrit anddecreased reticulocyte concentration and red cell distribution width(RDW), indicating improved erythropoiesis. In addition, Hbb th3/+ micereceiving Fpn inhibitors had significantly lower leucocyte counts inblood compared to the vehicle group, further demonstrating thebeneficial effect of Fpn inhibitors in correcting pathologically alteredparameters in the disease model. Therefore, Fpn inhibitors improvedsignificantly anemia and corrected blood composition in the mouse modelof thalassemia intermedia.

The inefficient erythropoiesis of Hbb th3/+ mice causes excessiveproliferation of erythroid precursors in spleen, leading tosplenomegaly. Treatment of Hbb th3/+ mice with Fpn inhibitors resultedin significant reduction in spleen weight, therefore highlighting thepotential of Fpn inhibitors to revert splenomegaly (Table 10).

The effect of Fpn inhibitors on erythropoiesis was studied by analyzingthe percentage of differentiating erythroid precursors in bone marrowand spleen using flow cytometry and Ter1n 19 (eBioscience, Cat. 17-5921)and CD44 (BioLegend, Cat. 103028) markers. Bone marrow or spleen cellsisolated from Hbb th3/+ mice treated with Fpn inhibitors containedsignificantly reduced percentage of the early erythroid precursorsproerythroblasts, basophilic, and polychromatic erythroblast andincreased percentage of mature erythrocytes compared to vehicle-treatedHbb th3/+ mice (Table 10). These data demonstrated that Fpn inhibitorsameliorated the inefficient erythropoiesis in Hbb th3/+ mice and are inagreement with the improved hematological parameters in blood.

Serum erythropoietin levels in Hbb th3/+ mice and patients withthalassemia are upregulated due to a feedback response to anemia,hypoxia and inefficient erythropoiesis (Guo et al. JCI, 2013). Hbb th3/+mice treated with Fpn inhibitors produced significantly less serumerythropoietin (DuoSet ELISA R&D Systems, Cat. DY959) compared to thevehicle group, most likely as a consequence of partially correctedanemia and improved erythropoiesis (Table 10).

Elevated erythropoietin levels in Hbb th3/+ mice induced overexpressionof erythroferrone, an erythroid regulator hormone known to suppresshepcidin (Kautz L. et al, Nat. Genet., 2014). In agreement with reducedserum erythropoietin, erythroferrone mRNA expression was significantlyreduced in spleens of Fpn inhibitor-treated Hbb th3/+ mice compared tothose administered with vehicle alone (Table 10). Erythroferrone isproduced by erythrocyte precursors proliferating massively in spleens ofHbb th3/+ mice as a consequence of extramedullar erythropoiesis.Therefore, the effect of Fpn inhibitors on erythroferrone expression inspleen is mediated by the improved erythropoiesis.

Increased iron demand due to inefficient erythropoiesis and chronicallylow hepcidin levels in patients with thalassemia causes organ ironloading and associated morbidities, such as hepatocellular carcinoma andheart failure (Rivella S. Haematologica, 2015). Hbb th3/+ mice absorbexcessive amounts of iron as a consequence of inadequately low hepcidinlevels relative to the high iron content in liver, spleen and kidney andincreased ferroportin expression in duodenum (Gardenghi S., Blood,2007). Total liver iron and ⁵⁸Fe content in organs of Hbb th3/+ micetreated with either vehicle or Fpn inhibitors were analyzed byinductively coupled plasma optical emission spectrometry (ICP-OES) andinductively coupled plasma mass spectrometry (ICP-MS), respectively.⁵⁸Fe concentrations in livers and spleens of Hbb th3/+ mice dosed withFpn inhibitors were significantly lower compared to those of vehicletreated mice, indicating that Fpn inhibitors prevent organ ironaccumulation (Table 10).

As Fpn inhibitors are systemically available, they are able to blockiron export in all ferroportin expressing tissues, including duodenum,spleen and liver. Accordingly, Fpn inhibitors are expected to preventiron absorption from duodenum, however, they could not removepre-existing iron in liver and spleen. Indeed, total liver iron in micetreated with Fpn inhibitor or vehicle remained unchanged (not shown).Importantly, Fpn inhibitors reduced significantly ⁵⁸Fe concentration inspleens and livers of Hbb th3/+ mice, demonstrating the ability of thesesmall molecules to prevent iron loading.

Additionally, reactive oxygen species (ROS) were detected in bone marrowcells using a fluorescent indicator, CM-H₂DCFDA (Thermo FisherScientific, Cat. C6827). Flow cytometric analysis showed that Fpninhibitors decreased significantly ROS in mature erythroid cellscompared to vehicle treated Hbb th3/+ mice (Table 10).

These data demonstrated the disease-modifying capacity of orallyadministered small molecular weight ferroportin inhibitors in improvinganemia and ineffective erythropoiesis, as well in reducing splenomegalyand preventing further liver and spleen iron loading in a disease modelof β-thalassemia intermedia.

TABLE 10 Exp. Comp. Exp. Comp. Exp. Comp. Exp. Comp. Parameter No. 1 No.2 No. 40 No. 127 Decrease in serum iron by 49/66% 50/69% 28/58% 68/81%20/60 mg/kg compound Correction of anemia at 6/20 g/d 3/11 g/L 6/13 g/L12/20 g/L day 20-48 by 20/60 mg/kg Increase in blood 4/8%  0/33%  2/22% 0/36% erythrocyte counts by 20/ 60 mg/kg compound Decrease in blood 8/39%  0/11% 19/43% 16/61% reticulocyte counts by 20/ 60 mg/kg compoundIncrease in hematocrit by 0/4%  0/15% 0/1%  3/20% 20/60 mg/kg compoundDecrease in RDW by 20/  3/16%  0/15% NA/NA 19/25% 60 mg/kg compoundDecrease in leukocyte 32/44% 29/55%  0/36% 46/66% counts by 20/60 mg/kgcompound Decreased in ROS in bone 20/45% 13/65% NA/NA   NA/75%  marrowerythrocytes Decrease in relative spleen 23/59% 16/47% 23/48% 40/61%weight by 20/60 mg/kg Decrease in ⁵⁸Fe spleen 14/48% 13/40% 19/51%43/68% iron content by 20/60 mg/kg compound Prevention of liver ⁵⁸Fe12/40% 14/47% 20/48% 39/59% loading by 20/60 mg/kg Decrease in serum64/78%  4/27%  6/37% 32/33% erythropoietin by 20/60 mg/kg compoundDecrease in spleen  82/292% 461/639% NA/NA   1012/3031% erythroferronemRNA by 20/60 mg/kg compound

Table 10. Efficacy of Ferroportin inhibitors in a mouse model ofthalassemia intermedia (Hbb th3/+ mice). The indicated Fpn inhibitorswere dosed twice daily for 20 days (Example Compound 1 and 2), 27 days(Example Compound 127) or 46 days (Example Compound 40). Data areexpressed as difference to the vehicle control group for hemoglobin andas % change to the vehicle control group for all other parameter shown

Preparation of Example Compounds General Experimental Details

Commercially available reagents and solvents (HPLC grade) were usedwithout further purification. ¹H NMR spectra were recorded on a BrukerDRX 500 MHz spectrometer, a Bruker DPX 250 MHz spectrometer or a BrukerAvance spectrometer 400 MHz in deuterated solvents. Chemical shifts (δ)are in parts per million.

Compounds were purified by flash column chromatography on normal phasesilica on Biotage Isolera systems using the appropriate SNAP cartridgeand gradient. Alternatively compounds were purified on reverse phaseusing Biotage Isolera systems with the appropriate C18 SNAP cartridgeand reverse-phase eluent or by preparative HPLC (if stated otherwise).

Analytical HPLC-MS Method A (MET/CR/1673)

Column Supelco Ascentis Express (Part No. 53802-U) 2.1 × 30 mm, 2.7 μmColumn Temp 40° C. Mobile Phase A, Water + 0.1% Formic acid B,Acetonitrile + 0.1% Formic acid Time (mins) % organic Gradient 0 5 1.5100 1.6 100 1.61 5 Flow rate 1 ml/min Injection Vol 3 μl DetectionSignal UV 215 PDA Spectrum Range: 210-420 nm step: 1 nm MSD Signalsettings Scan Pos (Shimadzu): 100-1000 Scan Pos (MS14): 130-850

Method B (MET/CR/1600)

Column Phenomenex Gemini-NX C18 (Part No. 00D-4453-B0) 2.0 × 100 mm, 3μm column Column Temp 40° C. Mobile Phase A, 2 mM amm. bicarbonate,buffered to pH 10 B, Acetonitrile Gradient Time (mins) % organic 0.00 55.50 100 5.90 100 5.92 5 Flow rate 0.5 ml/min Injection Vol 3 μlDetection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1 nm MSDSignal settings Scan Pos: 100-1000

Method C (MET/CR/1416)

Column Waters Atlantis dC18 (Part No. 186001295) 2.1 × 100 mm, 3 μmColumn Temp 40° C. Mobile Phase A, Water + 0.1% Formic acid B,Acetonitrile + 0.1% Formic acid Gradient Time (mins) % organic 0.00 55.00 100 5.40 100 5.42 5 Flow rate 0.6 ml/min Injection Vol 3 μlDetection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1 nm MSDSignal settings Scan Pos: 100-1000

Method D—(MET/uPLC/AB101)

Column Phenomenex Kinetix-XB C18 (Part No. 00D-4498-AN) 2.1 × 100 mm,1.7 μm Column Temp 40° C. Mobile Phase A, Water + 0.1% Formic acid B,Acetonitrile + 0.1% Formic acid Gradient Time (mins) % organic 0.00 55.30 100 5.80 100 5.82 5 Flow rate 0.6 ml/min Injection Vol 1 μlDetection Signal UV 215 PDA Spectrum Range: 200-400 nm step: 1 nm MSDSignal settings Scan Pos: 150-850

Method E—(MET/CR/1278)

Column Waters Atlantis dC18 (Part No. 186001291) 2.1 × 50 mm, 3 μmColumn Temp 40° C. Mobile Phase A, Water + 0.1% Formic acid B,Acetonitrile + 0.1% Formic acid Gradient Time (mins) % organic 0.00 52.50 100 2.70 100 2.71 5 3.50 5 Flow rate 1 ml/min Injection Vol 3 μlDetection Signal UV 215 PDA Spectrum Range: 210-420 nm step: 1 nm MSDSignal settings Scan Pos (Shimadzu): 100-1000 Scan Pos (MS14): 130-850

Method F—METICR/0990

Column Phenomenex Gemini-NX C18 (00B-4453-B0) 2.0 × 50 mm, 3 um ColumnTemp 40° C. Mobile Phase A, 2 mM Ammonium bicarbonate, buffered to pH 10B, Acetonitrile Gradient Time (mins) % organic 0.00 1 1.80 100 2.10 1002.30 1 3.50 1 Flow rate 1 ml/min Injection Vol 3 μl Detection Signal UV215 PDA Spectrum Range: 210-420 nm step: 1 nm MSD Signal settings ScanPos: 150-850

Method G—MET/CR/2044

Column Thermofisher Hypercarb ™ Porous Graphitic Carbon 2.1 mm × 50 mm,3 μm Column Temp 40° C. Mobile Phase A, 25 mM Ammonium acetate in HPLCgrade water pH~5 B, 25 mM Ammonium acetate in HPLC grade acetonitrileGradient Time (mins) % organic 0.00 2 4 100 5 100 6 2 6.5 2 Flow rate0.5 ml/min Injection Vol 3 μl Detection Signal UV 215 PDA SpectrumRange: 210-420 nm step: 1 nm MSD Signal settings Scan Pos: 150-850

Method H—METUPLCMS-A-004

Column Acquity UPLC BEH C18 2.1 mm × 50 mm, 1.7 μM Column Temp AmbientMobile Phase A, Water/acetonitrile, 9:1 + 0.1% formic acid B,Acetonitrile/water, 9:1 + 0.1% formic acid Gradient Time (mins) %organic 0.00 5 1.5 100 1.7 100 1.8 5 2.0 5 Flow rate 0.7 ml/minInjection Vol 4 μl Detection Signal UV 215 PDA Spectrum Range: 210-420nm MSD Signal settings Scan Pos: 150-800

Method I—METUPLCMS-A-006

Column Acquity UPLC HSS T3 2.1 mm × 100 mm, 1.8 μm Column Temp 40° C.Mobile Phase A, Water/acetonitrile, 9:1 + 0.1% formic acid B,Acetonitrile/water, 9:1 + 0.1% formic acid Gradient Time (mins) %organic 0.00 5 5.30 100 5.80 100 5.82 5 6.00 5 Flow rate 0.7 ml/minInjection Vol 4 μl Detection Signal UV 215 PDA Spectrum Range: 210-420nm MSD Signal settings Scan Pos: 150-800

Method J—METUPLCMS-A-007

Column Acquity UPLC BEH C18 2.1 × 100 mm, 1.7 μm Column Temp 40° C.Mobile Phase A, 2 mM Ammonium Bicarbonate B, Acetonitrile:2 mM AmmoniumBicarbonate (95:5) Gradient Time (mins) % organic 0.00 5 5.30 100 5.80100 5.82 5 6.00 5 Flow rate 0.6 ml/min Injection Vol 4 μl DetectionSignal UV 215 PDA Spectrum Range: 210-420 nm MSD Signal settings ScanPos: 150-800

Method K—MET/UPLCMS-A/013

Column Acquity UPLC HSS T3 2.1 × 100 mm, 1.8 μm Column Temp 40° C.Mobile Phase A, Water + 0.1% formic acid, acetonitrile + 0.1% formicacid (90:10) B, Acetonitrile + 0.1% formic acid, water + 0.1% formicacid (90:10) Gradient Time (mins) % organic 0.00 30 5.30 100 5.80 1005.82 30 6.00 30 Flow rate 0.6 ml/min Detection Signal UV 215 PDASpectrum Range: 210-420 nm MSD Signal settings Scan Pos: 150-800

Method L—MET-THERMOMS-B-015

Column X-bridge C-18 250 × 4.6 mm, 5 μm Column Temp NA Injection Vol. 10μl Mobile Phase A, 2 mM Ammonium Bicarbonate (pH−10)/ pH 10 adjustedusing liq. NH₃ B, Acetonitrile Gradient Time (mins) % organic 0.0 5 10.0100 10.5 100 11.0 5 12.0 5 Detection Signal UV 215 MSD Signal settingsScan Pos: 50-1000

Method M—MET/CR/1410

Column Phenomenex Kinetex Core-Shell C18 (Part No. 00D-4601-AN) 2.1 × 50mm, 5 μm Column Temp 40° C. Mobile Phase A, Water + 0.1% Formic acid B,Acetonitrile + 0.1% Formic acid Gradient Time (mins) % organic (B) 0.005 1.20 100 1.30 100 1.31 5 Flow rate 1.2 ml/min Injection Vol 3 μl

Preparative HPLC—Neutral pH Method

Column Waters Sunfire C18 (Part no. 186003971) 30 × 100 mm, 10 um ColumnTemp Room temperature Mobile Phase A, Water B, Acetonitrile GradientTime (mins) % organic 0 10 2 10 2.5 15 14.5 100 15.5 100 16 10 17 10Flow rate 40 ml/min Injection Vol 1500 μl Detection Signal UV 215

Preparative HPLC—Low pH Prep Method (Acid)

Column Waters Sunfire C18 (Part no. 186003971) 30 × 100 mm, 10 μm ColumnTemp Room temperature Mobile Phase A, Water + 0.1% Formic acid B,Acetonitrile + 0.1% Formic acid Gradient Time (mins) % organic 0 5 2 52.5 10 14.5 100 15.5 100 16 5 17 5 Flow rate 40 ml/min Injection Vol1500 μl Detection Signal UV 215

Preparative HPLC—High pH Prep Method (Basic)

Column Waters Xbridge C18 (Part no. 186003930) 30 × 100 mm, 10 μm ColumnTemp Room temperature Mobile Phase A, Water + 0.2% Ammonium hydroxide B,Acetonitrile + 0.2% Ammonium hydroxide Gradient Time (mins) % organic 05 2.5 5 16.05 95 18.2 95 19.1 5 20 5 Flow rate 40 ml/min Injection Vol1500 μl Detection Signal UV 215

Abbreviations

-   AcOH Acetic acid-   AIBN 2,2′-Azobis(2-methylpropionitrile)-   BH₃ Borane-   Boc₂O Di-tert-butyl dicarbonate-   CaCO₃ Calcium carbonate-   CBz Benzyloxy carbamate-   CDI 1,1′-Carbonyldiimidazole-   CHCl₃ Chloroform-   d Day(s)-   DAST N-ethyl-N-(trifluoro-lambda-4-sulfanyl)ethanamine-   DBU 1,8-Diazabicycloundec-7-ene-   DCC N,N′-dicyclohexylcarbodiimide-   DCE 1,2-Dichloroethane-   DCM Dichloromethane-   DIAD Diisopropyl azodicarboxylate-   DIPEA N,N-diisoproylethylamine-   DMAP N,N-dimethylpyridin-4-amine-   DMF N,N-dimethylformamide-   Et₂O Diethyl ether-   EtOAc Ethyl acetate-   EtOH Ethanol-   h Hour(s)-   HATU    1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-Oxide    Hexafluorophosphate-   HCl Hydrochloric acid-   HPLC High Performance Liquid Chromatography-   IPA Isopropyl alcohol-   K₂CO₃ Potassium carbonate-   KOtBu Potassium tert-butoxide-   KHMDS Potassium 1,1,1,3,3,3-hexamethyldisilazan-2-ide-   KHSO₄ Potassium bisulfate-   LiAlH₄ Lithium Aluminium Hydride-   LiCl Lithium chloride-   LiOH Lithium hydroxide-   MeCN Acetonitrile-   MeI Methyl iodide-   MeOH Methanol-   min Minute(s)-   MW Molecular weight-   NaBH₄ Sodium borohydride-   NaHCO₃ Sodium hydrogen carbonate-   NaH Sodium Hydride (60% in mineral oil)-   NaOH Sodium hydroxide-   NBS N-bromosuccinimide-   NCS N-chlorosuccinimide-   NH₄Cl Ammonium chloride-   Pd/C Palladium on carbon-   PdCl₂(dppf)    Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-   Pd₂dba₃ Tris(dibenzylideneacetone)dipalladium(0)-   PPh₃ Triphenylphosphine-   PTSA p-Toluenesulfonic acid-   TBME tert-butyl methyl ether-   TBSCl tert-Butyldimethylsilyl chloride-   TEA Triethylamine-   TFA Trifluoroacetic acid-   TMOF Trimethyl orthoformate-   Xantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Intermediates Scheme A Above: Tert-butylN-[(3-fluoropyridin-2-yl)methyl]carbamate (A1)

A suspension of 3-fluoropyridine-2-carbonitrile (8.0 g, 6.55 mmol),di-tert-butyl dicarbonate (15.7 g, 72.07 mmol), TEA (10.05 ml, 72.07mmol) in EtOH (300 ml) was purged with N₂. Pd/C (10% wt., 0.7 g, 6.55mmol) was added and the reaction mixture was stirred under an atmosphereof hydrogen for 16 h. The reaction mixture was filtered through celite,rinsed with MeOH (100 ml) and the filtrates were removed under vacuum toafford the crude product. Purification by flash column chromatography(gradient elution 0-70% EtOAc/heptane) afforded the title compound (11.3g, 72%) as an off-white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.41-8.31 (m, 1H), 7.65 (ddd, J=10.1,8.3, 1.3 Hz, 1H), 7.38 (dt, J=8.5, 4.4 Hz, 1H), 7.18 (s, 1H), 4.30 (d,J=5.4 Hz, 2H), 1.37 (s, 9H)

HPLCMS (Method A): [m/z]: 226.9 [M+H]⁺

(3-Fluoropyridin-2-yl)methanamine dihydrochloride (A2)

In a similar fashion to general procedure 2, tert-butylN-[(3-fluoropyridin-2-yl)methyl]carbamate (A1) (11.3 g, 47.45 mmol) and12M HCl (59.3 ml, 711.72 mmol) in MeOH (150 ml) at 40° C. for 2 h, gavethe title compound (9.7 g, 100%) as an off-white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.48 (dt, J=4.7, 1.3 Hz, 1H), 7.69(ddd, J=9.7, 8.5, 1.2 Hz, 1H), 7.50 (dt, J=8.8, 4.5 Hz, 1H), 4.37 (s,2H)

HPLCMS (Method A): [m/z]: 126.9 [M+H]⁺

Scheme B Above (4, 6-Dimethylpyridin-3-yl)methanamine hydrochloride (B1)

4,6-dimethylpyridine-3-carbonitrile (0.15 g, 1.135 mmol) in MeOH (150ml) was subjected to the H-Cube with 10% palladium on carbon at a flowrate of 1 ml/min using H₂ at 50 bar and room temperature into a solutionof 1M HCl (1 ml). The solvent was evaporated in vacuo to give the titlecompound (190 mg, 64%) as a white solid. Used without purification.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.74-8.66 (m, 1H), 8.62-8.42 (m, 3H),7.76-7.64 (m, 1H), 4.23-4.13 (m, 2H), 2.66-2.63 (m, 3H), 2.58-2.54 (m,3H)

HPLCMS (Method E): [m/z]: 136.9 [M+H]⁺

Scheme C Above 2-(Hydroxymethyl)benzonitrile (C1)

1M BH₃ in THF (1.51 ml) was added to an ice-cooled (0° C.) solution of3-formylpyridine-2-carbonitrile (200 mg, 1.51 mmol) in THF (5 ml). Thereaction was allowed to warm to room temperature and stirred for 15 h.The reaction was poured onto ice/water (25 ml). The aqueous layerextracted with EtOAc (3×20 ml). The combined organic layers were dried(Na₂SO₄), filtered and the solvent evaporated to give a brown oil.Purification by flash column chromatography (eluting with a gradient20-100% EtOAc/heptane) gave the titled compound (45.5 mg, 22.4%) as ayellow solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.55 (dd, J=4.7, 1.4 Hz, 1H), 8.01-7.95(m, 1H), 7.49 (dd, J=8.0, 4.7 Hz, 1H), 4.89 (s, 2H)

HPLCMS (Method A): [m/z]: 134.85 [M+H]⁺

2-{[(Tert-butyldimethylsilyl)oxy]methyl}benzonitrile (C2)

1 M TBSCl in DCM (0.369 ml, 0.369 mmol) was added dropwise to a solutionof 3-(hydroxymethyl)pyridine-2-carbonitrile (C1) (45 mg, 0.335 mmol) andimidazole (46 mg, 0.671 mmol) in DMF (2 ml). The reaction was stirred atroom temperature for 15 h. The solvent was evaporated and the crudeproduct purified by flash column chromatography (eluting with a gradientof 0-50% EtOAc-heptane) to give the titled compound (44 mg, 52.8%) as ayellow oil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.60-8.58 (m, 1H), 8.10-7.96 (m, 1H),7.53 (dd, J=8.0, 4.7 Hz, 1H), 4.94 (s, 2H), 0.95 (s, 9H), 0.15 (s, 6H)

HPLCMS (Method A): [m/z]: 249.00 [M+H]⁺

(3-{[(Tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methanamine (C3)

2M LiAlH₄ in THF (0.09 ml) was added dropwise to an ice-cooled solution(0° C.) of3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridine-2-carbonitrile (C2) (44mg, 0.18 mmol) in THF (3 ml). The reaction was allowed to warm to roomtemperature and stirred for 2 h. Diethyl ether (5 ml) was added followedby H₂O (1 ml), then 20% w/w NaOH (1 ml) and water (3 ml). The layersseparated. The aqueous layer was extracted with EtOAc (3×10 ml). Thecombined organic layers were dried (Na₂SO₄), filtered and the solventevaporated. The crude product was purified by flash columnchromatography (eluting with a gradient of 0-100% EtOAc/heptane) to givethe title compound (10 mg, 22.4%) as a yellow oil.

HPLCMS (Method A): [m/z]: 252.95 [M+H]⁺

N-(2-Nitrophenyl)prop-2-enamide (D)

To a stirring suspension of 2-nitroaniline (5.0 g, 36.2 mmol) and K₂COO₃(15.01 g, 108.6 mmol) in acetone (100 ml) at room temperature was addedacryloyl chloride (11.8 ml, 145 mmol) and the mixture stirred for 16 h.The reaction mixture was filtered and concentrated in vacuo to give thecrude product. Purification by flash column chromatography (gradientelution 10-15% EtOAc/heptane) afforded the title compound (6.95 g, 78%)as a yellow solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=10.59 (s, 1H), 8.90 (dd, J=8.6, 1.3 Hz,1H), 8.25 (dd, J=8.5, 1.6 Hz, 1H), 7.68 (ddd, J=8.5, 7.3, 1.4 Hz, 1H),7.21 (ddd, J=8.6, 7.3, 1.4 Hz, 1H), 6.54-6.28 (m, 2H), 5.89 (dd, J=9.9,1.3 Hz, 1H)

HPLCMS (Method A): [m/z]: 192.9 [M+H]⁺

2-(Chloromethyl)-5-(trifluoromethyl)-1H-1,3-benzodiazole (E)

12 M HCl (1 ml, 12 mmol) was added to a mixture of4-(trifluoromethyl)benzene-1,2-diamine (1 g, 5.68 mmol) and chloroaceticacid (0.590 g, 6.25 mmol) in water (20 ml) and the mixture was heated at100° C. for 2 h. Further 12 M HCl (4 ml, 48 mmol) was added and thereaction mixture heated at 120° C. for 3 h. The mixture was then cooledto room temperature and quenched by addition of 7 M ammonia in MeOHuntil basic, extracted with EtOAc (3×20 ml) and the combined organiclayers were washed with brine (20 ml), dried (MgSO₄), filtered andevaporated in vacuo. Flash column chromatography (eluting with agradient 5-50% EtOAc/heptane) afforded the crude title compound as apurple solid (0.571 g, 24%, 56% purity) which was used without furtherpurification.

HPLCMS (Method E): [m/z]: 234.85 [M+H]⁺

Tert-Butyl 2-(chloromethyl) methyl-1H-1,3-benzodiazole-1-carboxylate (F)

To the solution 2-(chloromethyl)-6-methyl-1H-1,3-benzodiazole (1 g, 6mmol) in DMF (20 ml) was added DIPEA (1.4 g, 11 mmol) followed byaddition of Boc anhydride (1.8 g, 8 mmol). The reaction was stirred for18 h. Water was added to the reaction and extracted with ethyl acetate.The organic phase was dried, Na₂SO₄, concentrated in vacuo to the crudeproduct which was purified by flash column chromatography using n-hexaneto ethyl acetate/n-hexane (5:95) to hexane to give the required productas a yellow oil (0.7 g, 22%). The required product was obtained as amixture which was not separable and used in the next step.

1H-NMR (CDCl₃, 400 MHz): d[ppm]=7.84 (d, J=8.7 Hz, 2H), 7.62 (d, J=8.2Hz, 1H), 7.53 (s, 1H), 7.20 (dd, J=13.0, 4.6 Hz, 2H), 5.05 (s, 2H), 5.04(s, 2H), 2.50 (s, 3H), 2.47 (s, 3H), 1.74 (s, 9H), 1.73 (s, 9H),

N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G)

To an N₂ purged suspension of 3-fluoro-2-nitroaniline (500 mg, 3.20mmol) and K₂CO₃ (1.33 g, 9.61 mmol) in acetone (10 ml) was addedprop-2-enoyl chloride dropwise (1.0 ml, 12.8 mmol). The reaction mixturewas left stirring at room temperature for 16 h. The reaction wasfiltered, concentrated in vacuo and purified by flash columnchromatography (eluting with a gradient of 0-70% EtOAc/heptane) toafford the title compound (604 mg, 87%) as a yellow solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=10.58 (s, 1H), 7.69 (m, 1H), 7.46-7.33(m, 2H), 6.43 (dd, J=17.0, 9.8 Hz, 1H), 6.27 (dd, J=17.0, 2.1 Hz, 1H),5.85 (dd, J=9.8, 2.1 Hz, 1H)

HPLCMS (Method A): [m/z]: 210.95 [M+H]⁺

N-(3-chloro-2-nitrophenyl)prop-2-enamide (H)

Acryloyl chloride (1.03 ml, 12.67 mmol) was slowly added to a suspensionof 3-chloro-2-nitroaniline (0.729 g, 4.22 mmol) and K₂COO₃ (2.34 g, 16.9mmol) in acetone (20 ml). The reaction mixture was stirred at roomtemperature for 4 h, filtered and the residue was rinsed with acetone.The combined filtrates were evaporated in vacuo. Purification by flashcolumn chromatography (eluting with a gradient of 0-60% EtOAc/heptane)afforded the title compound (0.52 g, 47%) as a yellow solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.36 (dd, J=8.3, 1.1 Hz, 1H), 8.28 (s,1H), 7.49 (dd, J=8.3, 8.3 Hz, 1H), 7.32 (dd, J=8.3, 1.1 Hz, 1H), 6.47(dd, J=16.9, 0.8 Hz, 1H), 6.25 (dd, J=16.9, 10.3 Hz, 1H), 5.90 (dd,J=10.3, 0.8 Hz, 1H)

HPLCMS (Method M): [m/z]: 227.00 [M+H]⁺

N-(2-methoxy-6-nitrophenyl)prop-2-enamide (I)

To an N₂ purged stirring suspension of 2-methoxy-6-nitroaniline (0.52 g,3.09 mmol) and K₂COO₃ (1.71 g, 12.4 mmol) in acetone (30 ml) was addedacryloyl chloride (0.754 ml, 9.28 mmol) dropwise. The reaction mixturewas left stirring at room temperature for 16 h. The mixture wasfiltered, concentrated, diluted with EtOAc, washed with water, dried(MgSO₄), filtered and concentrated to give the crude product.Purification by flash column chromatography (eluting with a gradient of0-100% EtOAc/heptane followed by 0-2% MeOH/EtOAc) afforded the titlecompound (0.674 g, 96%) as an orange solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.82 (s, 1H), 7.57 (dd, J=8.2, 1.3 Hz,1H), 7.31 (t, J=8.3 Hz, 1H), 7.19 (dd, J=8.3, 1.3 Hz, 1H), 6.47 (dd,J=17.0, 1.7 Hz, 1H), 6.33 (dd, J=17.0, 9.8 Hz, 1H), 5.85 (dd, J=9.8, 1.7Hz, 1H), 3.97 (s, 3H)

HPLCMS (Method M): [m/z]: 223.05 [M+H]⁺

N-(5-fluoro-2-nitrophenyl)prop-2-enamide (J)

Acryloyl chloride (3.8 ml, 46.5 mmol) was added slowly to a suspensionof 5-fluoro-2-nitroaniline (2.4 g, 15.5 mmol) and K₂COO₃ (8.57 g, 62mmol) in acetone (100 ml) and the mixture was stirred at roomtemperature for 3 d and at reflux for 6 h. Further acryloyl chloride(3.8 ml, 46.5 mmol) and DMAP (0.95 g, 7.75 mmol) were added and themixture heated at reflux for a further 2 h. The reaction mixture wascooled to room temperature and filtered. The residue was rinsed withacetone and the combined filtrates evaporated under vacuum. Theresultant residue was re-dissolved in Et₂O (350 ml) and saturated NaHCO₃(aq) (200 ml). The mixture was stirred vigourously for 15 min. Thephases were separated and the organic phase washed with a furtherportion of saturated NaHCO₃ (aq) (100 ml) and brine (100 ml), dried(sodium sulphate) and evaporated under vacuum. Purification by flushingthrough a plug of silica (eluting with a gradient of 0-4% Et₂O/heptane)afforded the title compound (1.04 g, 32%) as a pale yellow solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=10.83 (s, 1H), 8.79 (dd, J=11.2, 2.5 Hz,1H), 8.34 (dd, J=9.2, 5.7 Hz, 1H), 6.99-6.82 (m, 1H), 6.53 (d, J=16.9Hz, 1H), 6.35 (dd, J=17.1, 9.9 Hz, 1H), 5.95 (d, J=10.1 Hz, 1H)

HPLCMS (Method M): [m/z]: 211.15 [M+H]⁺

General Scheme K-I Above N-(2-chloro-5-fluorophenyl)prop-2-enamide (K1)

To an N₂ purged suspension of 2-chloro-5-fluoroaniline (3.0 g, 20.6mmol) and K₂CO₃ (11.4 g, 82.4 mmol) in acetone (80 ml) at roomtemperature was added dropwise prop-2-enoyl chloride (5.0 ml, 61.8 mmol)and stirred for 16 h. The reaction mixture was filtered, concentrated invacuo and purified by flash column chromatography (eluting with agradient of 0-35% EtOAc/heptane) to afford the title compound (3.99 g,84%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.40 (dd, J=10.9, 3.0 Hz, 1H), 7.79 (s,1H), 7.35 (dd, J=8.9, 5.6 Hz, 1H), 6.81 (ddd, J=8.9, 7.6, 3.0 Hz, 1H),6.50 (dd, J=16.9, 1.2 Hz, 1H), 6.32 (dd, J=16.9, 10.0 Hz, 1H), 5.88 (dd,J=10.0, 1.2 Hz, 1H)

HPLCMS (Method A): [m/z]: 200.10 [M+H]⁺

N-(6-chloro-3-fluoro-2-nitrophenyl)prop-2-enamide (K2)

To an N₂ purged solution of N-(2-chloro-5-fluorophenyl)prop-2-enamide(K1) (3.99 g, 17.4 mmol), concentrated H₂SO₄ (15 ml) and AcOH (6 ml) at0° C. was added red fuming HNO₃ (1.8 ml, 38.3 mmol) dropwise and thereaction was left stirring for 2 h. The reaction mixture was poured ontoice water and extracted using DCM (4×40 ml). The combined organicextracts were dried (MgSO₄), filtered, concentrated in vacuo andpurified by flash column chromatography (eluting with a gradient of0-70% EtOAc/heptane) to give the title compound (1.08 g, 20%) as a whitesolid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.64 (dd, J=9.1, 5.0 Hz, 1H), 7.51 (s,1H), 7.19 (m, 1H), 6.52 (dd, J=16.9, 1.1 Hz, 1H), 6.32 (dd, J=16.9, 10.2Hz, 1H), 5.94 (dd, J=10.1, 1.1 Hz, 1H)

HPLCMS (Method A): [m/z]: 244.95 [M+H]+

N-(2,4-difluorophenyl)prop-2-enamide (K3)

To an N₂ purged suspension of 2,4-difluoroaniline (2 g, 1.49 mmol) andK₂COO₃ (8.56 g, 61.7 mmol) in acetone (60 ml) at room temperature wasadded prop-2-enoyl chloride (3.7 ml, 46.5 mmol) dropwise. The reactionmixture was left stirring for 16 h. The reaction was filtered,concentrated, purified by flash column chromatography (eluting with agradient of 0-30% EtOAc/heptane) and triturated with heptane to give thetitle compound (2.9 g, 100%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.49-8.29 (m, 1H), 7.33 (s, 1H),6.99-6.84 (m, 2H), 6.48 (dd, J=16.9, 1.4 Hz, 1H), 6.29 (dd, J=16.8, 10.1Hz, 1H), 5.85 (dd, J=10.1, 1.4 Hz, 1H)

HPLCMS (Method A): [m/z]: 183.95 [M+H]⁺

N-(2,4-difluoro-6-nitrophenyl)prop-2-enamide (K4)

To an N₂ purged solution of N-(2,4-difluorophenyl)prop-2-enamide (K3)(2.9 g, 15.4 mmol), AcOH (5 ml) and concentrated H₂SO₄ (13 ml) at 0° C.was added red fuming nitric acid (1.6 ml) dropwise. The reaction mixturewas left stirring for 2 h. The reaction was poured onto ice water andthe resulting solution extracted using DCM (4×40 ml). The combinedorganic extracts were washed with brine, dried (MgSO₄), filtered,concentrated in vacuo and triturated with heptane to give the crudeproduct as a beige solid (3.23 g). Purification by flash columnchromatography (eluting with a gradient of 0-40% EtOAc/heptane) gave thetitle compound (1.25 g, 35.5%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.17 (s, 1H), 7.67 (dt, J=7.9, 2.4 Hz,1H), 7.34-7.28 (m, 1H), 6.51 (dd, J=17.0, 1.4 Hz, 1H), 6.35 (dd, J=17.0,9.9 Hz, 1H), 5.92 (dd, J=9.9, 1.3 Hz, 1H)

HPLCMS (Method A): [m/z]: 229.05 [M+H]+

N-(2,5-difluorophenyl)prop-2-enamide (K5)

To an N₂ purged stirring solution of 2,5-difluoroaniline (1.5 ml, 15.5mmol) and K₂COO₃ (6.42 g, 46.5 mmol) in acetone (60 ml) at roomtemperature was added prop-2-enoyl chloride (5.0 ml, 61.96 mmol)dropwise. The reaction mixture was left stirring at room temperature for2 h. The reaction was filtered and the filtrate concentrated to give awhite solid, which was triturated with heptane to give the titlecompound (2.91 g, quantitative) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.30 (m, 1H), 7.50 (s, 1H), 7.07 (m,1H), 6.85-6.70 (m, 1H), 6.50 (dd, J=16.8, 1.2 Hz, 1H), 6.30 (dd, J=16.9,10.1 Hz, 1H), 5.87 (dd, J=10.1, 1.2 Hz, 1H)

HPLCMS (Method A): [m/z]: 183.95 [M+H]⁺

N-(3,6-difluoro-2-nitrophenyl)prop-2-enamide (K6)

To an N₂ purged stirring solution ofN-(2,5-difluorophenyl)prop-2-enamide (K5) (2.91 g, 15.9 mmol), AcOH (5ml) and concentrated H₂SO₄ (13 ml) at 0° C. was added red fuming HNO₃(1.6 ml, 34.0 mmol) dropwise. The reaction mixture was left stirring for2 h. The reaction was poured onto ice water and the resulting solutionwas extracted using DCM (4×40 ml). The combined organic extracts werewashed with brine, dried (MgSO₄), filtered and concentrated in vacuo.Purification by flash column chromatography (eluting with a gradient of0-60% EtOAc/heptane), followed by flash column chromatography (elutingwith a gradient of 20% EtOAc/heptane) gave the title compound (0.316 g,8%) as a white solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=7.64 (s, 1H), 7.39 (m, 1H), 7.19 (m,1H), 6.51 (dd, J=17.0, 0.7 Hz, 1H), 6.32 (dd, J=17.0, 10.4 Hz, 1H), 5.93(dd, J=10.4, 0.7 Hz, 1H)

HPLCMS (Method A): [m/z]: 228.95 [M+H]⁺

N-[2-(trifluoromethyl)phenyl]prop-2-enamide (K7)

To an N₂ purged suspension solution of 2-(trifluoromethyl)aniline (3.1ml, 24.83 mmol) and K₂CO₃ (10.3 g, 74.48 mmol) in acetone (90 ml) wasadded prop-2-enoyl chloride (8.0 ml, 99.30 mmol) dropwise. The reactionmixture was left stirring at room temperature for 3 h. The reaction wasfiltered, concentrated in vacuo and triturated with heptane to affordthe title compound (4.74 g, 86%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.34 (d, J=8.2 Hz, 1H), 7.70-7.45 (m,3H), 7.28-7.22 (m, 1H), 6.46 (dd, J=16.9, 1.3 Hz, 1H), 6.29 (dd, J=16.9,10.0 Hz, 1H), 5.86 (dd, J=10.0, 1.3 Hz, 1H)

HPLCMS (Method A): [m/z]: 215.90 [M+H]⁺

N-[2-nitro-6-(trifluoromethyl)phenyl]prop-2-enamide (K8)

To an N₂ purged solution of N-[2-(trifluoromethyl)phenyl]prop-2-enamide(K7) (4.64 g, 20.91 mmol), AcOH (5 ml) and concentrated H₂SO₄ (13 ml) at0° C. was added red fuming HNO₃ (1.6 ml, 34.05 mmol) dropwise. Thereaction mixture was left stirring at room temperature for 16 h. Thereaction was poured onto ice water and then extracted using DCM (4×40ml). The combined organic extracts were dried (MgSO₄), filtered andconcentrated in vacuo. Purification by flash column chromatography(eluting with a gradient of 0-20% EtOAc/heptane) gave the title compound(0.829 g, 12%) as a beige solid.

HPLCMS (Method A): [m/z]: 260.95 [M+H]⁺

N-(2,3-Difluorophenyl)prop-2-enamide (K9)

To an N₂ purged solution of 2,3-difluoroaniline (3 ml, 31 mmol) andK₂CO₃ (12.9 g, 92.9 mmol) in acetone (120 ml) at room temperature wasadded dropwise prop-2-enoyl chloride (10 ml, 124 mmol). The reactionmixture was left stirring for 16 h. The reaction was filtered and thefiltrate concentrated to give a white solid which was triturated fromheptane to give the title compound (4.97 g, 87%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.29-8.12 (m, 1H), 7.46 (s, 1H),7.18-7.04 (m, 1H), 7.02-6.85 (m, 1H), 6.50 (dd, J=16.8, 1.3 Hz, 1H),6.31 (dd, J=16.9, 10.1 Hz, 1H), 5.87 (dd, J=10.1, 1.3 Hz, 1H)

HPLCMS (Method A): [m/z]: 184.2 [M+H]⁺

N-(2,3-Difluoro-6-nitrophenyl)prop-2-enamide (K10)

To an N₂ purged solution of N-(2,3-difluorophenyl)prop-2-enamide (K9)(4.9 g, 26.8 mmol), AcOH (5 ml) and concentrated H₂SO₄ (13 ml) at 0° C.was added nitric acid (1.6 ml) dropwise. The reaction mixture was leftstirring for 2 h. The reaction was poured onto ice/water and thesolution extracted using DCM (5×30 ml). The combined organic extractswere washed with brine (50 ml), dried over MgSO₄, filtered andconcentrated to give the crude product. This was triturated with heptane(100 ml). The suspension was filtered and the residue collected to givea mixture of both para/ortho nitrated regioisomers as a beige solid (6g). Purification by acidic prep-HPLC gave the title compound (4.2 g) asa white solid.

HPLCMS (Method A): [m/z]: 228.95 [M+H]⁺

General Scheme K-II Above N-(4-Cyanophenyl)prop-2-enamide (K11)

Acryloyl chloride (0.69 ml, 8.46 mmol) was added to an ice-coldsuspension of 4-aminobenzonitrile (250 mg, 2.12 mmol) and K₂COO₃ (880mg, 6.35 mmol) in acetone (5 ml). The mixture was stirred for 18 hwhilst warming to room temperature. The reaction mixture was filteredand the residue rinsed with acetone (5 ml). The combined filtrates wereevaporated in vacuo and the crude purification by flash columnchromatography using an elution gradient 0-80% EtOAc/heptane to affordthe title compound (353 mg, 96%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.73 (d, J=8.8 Hz, 2H), 7.68-7.58 (m,2H), 7.37 (s, 1H), 6.49 (dd, J=16.8, 1.0 Hz, 1H), 6.25 (dd, J=16.8, 10.2Hz, 1H), 5.86 (dd, J=10.2, 1.0 Hz, 1H)

HPLCMS (Method M): [m/z]: 173.45 [M+H]⁺

N-(4-Cyano-2-nitrophenyl)prop-2-enamide K12)

Nitric acid (0.6 ml) was added dropwise to an ice-cold solution ofN-(4-cyanophenyl)prop-2-enamide (K11) (1.03 g, 5.75 mmol) in acetic acid(2 ml) and sulfuric acid (4.75 ml). The reaction mixture was stirred for3 h, then poured into ice-cold water and the mixture extracted with DCM(4×20 ml). The combined organic extracts were dried (MgSO₄) andevaporated in vacuo. Purification by flash column chromatography usingan elution gradient 0-90% EtOAc/heptane afforded the title compound (1.2g, 93%) as a yellow solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=10.77 (s, 1H), 9.14 (d, J=8.9 Hz, 1H),8.58 (d, J=2.0 Hz, 1H), 7.90 (dd, J=8.9, 1.7 Hz, 1H), 6.54 (dd, J=17.0,0.9 Hz, 1H), 6.35 (dd, J=17.0, 10.1 Hz, 1H), 5.98 (dd, J=10.1, 0.9 Hz,1H)

Tert-butyl 2-(chloromethyl)-1H-1,3-benzodiazole-1-carboxylate (L)

A mixture of 2-(chloromethyl)-1H-1,3-benzodiazole (10 g, 0.06 mol),BOC₂O (18 ml, 0.06 mol) and TEA (6.07 g, 0.06 mol) in DCM (304 ml) wascooled to 0° C. A catalytic amount of DMAP (0.73 g, 0.006 mol) was addedand the reaction mixture was stirred at room temperature for 2 h. Themixture was diluted with EtOAc (150 ml), washed with saturated NaHCO₃(150 ml), brine (150 ml), dried (Na₂SO₄), filtered and concentrated togive the crude product. Purification by flash column chromatography(eluting with a gradient of 5-10% EtOAc/heptane) gave the title compound(7 g, 44%) as an off white oil.

HPLCMS (Method H): [m/z]: 167.2 [M-Boc+H]⁺

General Scheme I-1 Above Ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1,3-thiazole-5-carboxylate(208)

In a similar fashion to general procedure 1, a suspension of tert-butyl(3-amino-3-thioxopropyl)carbamate (1.0 g, 5.34 mmol), CaCO₃ (0.29 g,2.93 mmol) and ethyl 2-chloro-3-oxobutanoate (0.81 ml, 5.86 mmol) inEtOH (15 ml) was heated at 60° C. for 18 h. The reaction mixture wascooled to room temperature and concentrated in vacuo. The residue waspartitioned between EtOAc and water and the phases were separated. Theaqueous phase was extracted with EtOAc (2×80 ml) and the combinedorganic extracts were washed with brine (80 ml). The organic phase wasdried (Na₂SO₄), filtered and evaporated in vacuo. Purification by flashcolumn chromatography (eluting with a gradient of 5-50% EtOAc/heptane)afforded the title compound (1.57 g, 94%) as a white solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=5.01 (br s, 1H), 4.34 (q, J=7.1 Hz, 2H),3.57 (dt, J=5.5, 5.5 Hz, 2H), 3.15 (t, J=6.3 Hz, 2H), 2.73 (s, 3H), 1.47(s, 9H), 1.38 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 315.10 [M+H]⁺

Ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-5-carboxylate(209)

In a similar fashion to general procedure 1, Tert-butylN-(2-carbamothioylethyl)carbamate (1 g, 4.89 mmol), calcium carbonate(0.27 g, 3 mmol) and ethyl 2-chloro-3-oxopropanoate (0.81 g, 5 mmol)were combined in EtOH (15 ml) and the mixture heated at 60° C. for 18 h.Further 2-chloro-3-oxopropanoate (0.81 g, 5 mmol) was added and themixture further heated at 80° C. for 5 h. The reaction mixture wascooled to room temperature and concentrated in vacuo. The residue waspartitioned between water and EtOAc and the mixture extracted with EtOAc(3×80 ml). The combined organic extracts were washed with brine (80 ml),dried (Na₂SO₄), filtered and evaporated in vacuo. Purification by flashcolumn chromatography (eluting with a gradient of 20-60% EtOAc/heptane)afforded the crude title compound (743 mg) as a brown oil which was usedinto the next step without further purification.

HPLCMS (Method A): [m/z]: 301.05 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1,3-thiazole-5-carboxylicacid (210)

In a similar fashion to general procedure 5, ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1,3-thiazole-5-carboxylate(208) (1.57 g, 4.99 mmol) and LiOH (0.72 g, 30 mmol) in THF (30 ml) andwater (15 ml) afforded the title compound (1.23 g, 86%) as a whitesolid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=6.99 (t, J=5.3 Hz, 1H), 3.28 (m, 2H),3.04 (t, J=6.7 Hz, 2H), 2.58 (s, 3H), 1.37 (s, 9H)

HPLCMS (Method A): [m/z]: 287.05 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-5-carboxylic acid(211)

In a similar fashion to general procedure 5, crude ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-5-carboxylate(209) (743 mg, 2.47 mmol) and LiOH (300 mg, 12 mmol) in THF (20 ml) andwater (10 ml) afforded the crude title compound (500 mg) as a brown oil,which was used into the next step without further purification.

HPLCMS (Method A): [m/z]: 273.05 [M+H]⁺

Tert-butylN-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-4-methyl-1,3-thiazol-2-yl)ethyl]carbamate(212)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1,3-thiazole-5-carboxylicacid (210) (0.457 g, 1.6 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.349 g, 1.76 mmol), DIPEA (0.92 ml, 5 mmol) andHATU (0.73 g, 2 mmol) in DCM (20 ml) afforded the crude title compound(1.26 g) as a colourless oil.

HPLCMS (Method A): [m/z]: 395.1 [M+H]⁺

Tert-butylN-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(213)

In a similar fashion to general procedure 6, crude2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-5-carboxylic acid(211) (500 mg), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2)(402 mg, 2.02 mmol), DIPEA (1.06 ml, 6 mmol) and HATU (840 mg, 2 mmol)in DCM (30 ml) afforded the crude title compound (953 mg, 87% purity) asa yellow residue after partial purification by flash columnchromatography (eluting with a gradient of 20-100% EtOAc/heptanefollowed by 0-10% MeOH/EtOAc).

HPLCMS (Method A): [m/z]: 381.05 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-4-methyl-1,3-thiazole-5-carboxamide(214)

In a similar fashion to general procedure 2, crude tert-butylN-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-4-methyl-1,3-thiazol-2-yl)ethyl]carbamate(212) (1.26 g) and 12 M HCl (2 ml) in MeOH (20 ml) afforded the titlecompound freebase (471 mg) as a white solid after purification using anSCX-2 cartridge, rinsing with DCM and MeOH, then eluting with 7 Nammonia in MeOH.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.56 (t, J=5.5 Hz, 1H), 8.39 (dt,J=4.6, 1.3 Hz, 1H), 7.73-7.67 (m, 1H), 7.43-7.38 (m, 1H), 4.61-4.56 (m,2H), 3.03 (t, J=7.0 Hz, 2H), 2.95 (t, J=6.5 Hz, 2H), 2.54 (s, 3H)

HPLCMS (Method A): [m/z]: 295.05 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide(215)

In a similar fashion to general procedure 2, crude tert-butylN-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(213) (87%, 923 mg, 2.11 mmol) and 12 M HCl (2 ml) in MeOH (20 ml)afforded the title compound freebase (389 mg) as a yellow residue afterpurification using an SCX-2 cartridge, rinsing with DCM and MeOH, theneluting with 7 N ammonia in MeOH.

HPLCMS (Method A): [m/z]: 280.95 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-4-methyl-1,3-thiazole-5-carboxamide(Example Compound No. 7)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-4-methyl-1,3-thiazole-5-carboxamide(214) (471 mg, 1.6 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (295 mg,1.54 mmol) and DBU (0.26 ml, 2 mmol) gave the crude intermediate whichwas further reacted with iron powder (280 mg, 5 mmol) in AcOH (5 ml) togive the title compound (115 mg, 20%) as a white solid afterpurification by basic prep-HPLC followed by flash column chromatography(eluting with a gradient of 0-30% MeOH/DCM).

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.38 (d, J=4.7 Hz, 1H), 7.61 (t,J=9.2 Hz, 1H), 7.52-7.46 (m, 2H), 7.43-7.38 (m, 1H), 7.22-7.15 (m, 2H),4.73 (s, 2H), 3.22-3.14 (m, 4H), 3.14-3.05 (m, 4H), 2.51 (s, 3H)

HPLCMS (Method C): [m/z]: 439.1 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide(Example Compound No. 8)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-5-carboxamide(215) (389 mg, 1.39 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (267 mg,1.39 mmol) and DBU (0.25 ml, 2 mmol) in MeCN (15 ml) afforded a crudeintermediate which was further reacted with iron powder (230 mg, 4 mmol)in AcOH (5 ml) to afford the title compound (49 mg, 11%) as a whitesolid after three purifications by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.38 (dt, J=4.9, 1.3 Hz, 1H), 8.14(s, 1H), 7.65-7.59 (m, 1H), 7.52-7.47 (m, 2H), 7.44-7.39 (m, 1H),7.21-7.17 (m, 2H), 4.75 (d, J=1.6 Hz, 2H), 3.23 (t, J=6.8 Hz, 2H),3.15-3.07 (m, 6H)

HPLCMS (Method C): [m/z]: 425.1 [M+H]⁺

General Scheme 24 Above Methyl 3-amino-2-hydroxypropanoate hydrochloride(332)

Thionyl chloride (1.8 ml, 20 mmol) was added dropwise to ice-cold MeOH(60 ml) and stirred for 5 min. 3-Amino-2-hydroxypropanoic acid (1.04 g,9.9 mmol) was added and the reaction mixture stirred at room temperaturefor 18 h. The reaction mixture was rigourously evaporated in vacuo toafford the title compound (1.54 g, quant.) as a yellow oil.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.12 (s, 3H), 6.36 (s, 1H), 4.39 (dt,J=8.8, 4.6 Hz, 1H), 3.69 (s, 3H), 3.24-3.05 (m, 1H), 3.00-2.84 (m, 1H)

Methyl 3-(3-{[(tert-butoxy)carbonyl]amino}roxypropanoate (333)

In a similar fashion to general procedure 13, methyl3-amino-2-hydroxypropanoate hydrochloride (332) (4.35 g, 27.96 mmol),3-{[(tert-butoxy)carbonyl]amino}propanoic acid (5.82 g, 30.76 mmol), TEA(4.68 ml, 34 mmol) and DCC (5.77 g, 28 mmol) in DCM (80 ml) afforded thetitle compound (5.12 g, 63%) as a pale yellow oil after purification byflash column chromatography (eluting with a gradient 0-100%EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=6.06 (s, 1H), 5.18 (s, 1H), 4.32 (q,J=4.9 Hz, 1H), 3.83 (s, 3H), 3.72-3.60 (m, 2H), 3.46 (d, J=5.4 Hz, 1H),3.45-3.38 (m, 2H), 2.47-2.36 (m, 2H), 1.46 (s, 9H)

HPLCMS (Method A): [m/z]: 313.00 [M+Na]⁺

Methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4,5-dihydro-1,3-oxazole-5-carboxylate(334)

In a similar fashion to general procedure 14, methyl3-(3-{[(tert-butoxy)carbonyl]amino}propanamido)-2-hydroxypropanoate(333) (3.63 g, 12.5 mmol), DAST (1.98 ml, 15 mmol) and K₂COO₃ (3.46 g,25 mmol) in DCM (100 ml) afforded the title compound (3.4 g, 99%) as acolourless oil after purification by flash column chromatography(eluting with a gradient 40-100% EtOAc/heptane).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=4.96 (dd, J=10.8, 6.5 Hz, 1H), 4.24-4.09(m, 1H), 4.04-3.88 (m, 1H), 3.83 (s, 3H), 3.58-3.38 (m, 2H), 2.57 (d,J=4.8 Hz, 2H), 1.47 (s, 9H)

HPLCMS (Method M): [m/z]: 272.95 [M+H]⁺

General Procedure 16: Methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-5-carboxylate(335)

A solution of methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4,5-dihydro-1,3-oxazole-5-carboxylate(334) (3.2 g, 11.75 mmol), NBS (2.3 g, 12.93 mmol) and AIBN (0.19 g,1.18 mmol) in DCE (30 ml) was heated at 80° for 1.5 h. The reactionmixture was cooled to room temperature, quenched with saturatedNaHCO₃(aq) and extracted with DCM (3×80 ml). The combined organicextracts were dried (Na₂SO₄), filtered and evaporated in vacuo.Purification by flash column chromatography (eluting with a gradient of0-80% EtOAc/heptane) afforded the crude title compound (1.25 g, 29%, 75%purity) as an orange residue. Compound was used in the next step withoutfurther purification.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.69 (s, 1H), 5.17-4.98 (m, 1H), 3.94(s, 3H), 3.62 (q, J=6.2 Hz, 2H), 3.05 (t, J=6.2 Hz, 2H), 1.46 (s, 9H)

HPLCMS (Method M): [m/z]: 271.00 [M+H]⁺

2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-5-carboxylic acid(336)

In a similar fashion to general procedure 5, crude methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-5-carboxylate(335) (1.24 g, 3.44 mmol, 75% purity) and LiOH (0.329 mg, 13.76 mmol) inTHF (20 ml) and water (20 ml) afforded the title compound (0.51 g, 44%)as a pale orange residue. Compound was used in the next step withoutfurther purification.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.76 (s, 1H), 5.14 (s, 1H), 3.71-3.56(m, 2H), 3.09 (t, J=6.2 Hz, 2H), 1.46 (s, 9H)

HPLCMS (Method M): [m/z]: 256.95 [M+H]⁺

Tert-butylN-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate(337)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-5-carboxylic acid(336) (513 mg, 2 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (479 mg, 2.4 mmol), DIPEA (1.15 ml, 6.61 mmol) andHATU (837 mg, 2.2 mmol) in DCM (20 ml) afforded the crude title compound(1.08 g, 74%, 50% purity) as a yellow residue. Compound was used in thenext step without purification.

HPLCMS (Method M): [m/z]: 365.05 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(338)

In a similar fashion to general procedure 2, crude tert-butylN-[2-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate(337) (1.08 g, 1.48 mmol) and 12M HCl (1 ml) in MeOH (10 ml) affordedthe title compound freebase (444 mg, 57%) as a pale yellow solid afterfreebasing using an SCX-2 cartridge (10 g), rinsing with DCM and MeOH,then elution with 7N ammonia in MeOH.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.99 (t, J=5.7 Hz, 1H), 8.39 (dt,J=4.6, 1.5 Hz, 1H), 7.78-7.64 (m, 2H), 7.48-7.36 (m, 1H), 4.61 (dd,J=5.8, 1.6 Hz, 2H), 3.07-2.86 (m, 4H)

HPLCMS (Method M): [m/z]: 264.95 [M+H]⁺

2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide Example Compound No. 1)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(338) (444 mg, 1.68 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (323 mg,1.68 mmol) and DBU (301 μl, 2.02 mmol) in MeCN (10 ml) gave a crudeintermediate which was further reacted with iron powder (343 mg, 6.13mmol) and AcOH (10 ml) to give the title compound as a pale yellow solid(166 mg, 25%) after purification by flash column chromatography (elutingwith a gradient of 0-40% MeOH/DCM) followed by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.12 (s, 1H), 8.96 (t, J=5.8 Hz, 1H),8.38 (dt, J=4.6, 1.4 Hz, 1H), 7.73-7.66 (m, 2H), 7.53-7.37 (m, 3H), 7.11(dt, J=6.0, 3.5 Hz, 2H), 4.61 (dd, J=5.7, 1.4 Hz, 2H), 3.04-2.89 (m, 8H)

HPLCMS (Method B): [m/z]: 409.1 [M+H]⁺

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide (Example Compound No. 4)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(338) (250 mg, 0.83 mmol, 88% purity), 1H-benzimidazole-2-carbaldehyde(170 mg, 1.17 mmol), DIPEA (0.44 ml, 2.5 mmol) and MgSO₄ (150 mg, 1.25mmol) in MeOH (10 ml) at room temperature for 16 h gave an intermediatewhich was further reacted with NaBH₄ (47 mg, 1.25 mmol) to give thetitle compound (156 mg, 48%) as a white solid after purification byflash column chromatography [eluting with a gradient of 0-5% (7N NH₃ inMeOH)/DCM] followed by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (br s, 1H), 8.95 (t, J=5.8 Hz,1H), 8.39-8.34 (m, 1H), 7.72-7.65 (m, 2H), 7.54-7.46 (m, 1H), 7.46-7.36(m, 2H), 7.17-7.06 (m, 2H), 4.63-4.56 (m, 2H), 3.93 (s, 2H), 3.02-2.94(m, 4H), 2.57 (br s, 1H)

HPLCMS (Method D): [m/z]: 395.2 [M+H]⁺

General Scheme 27 Above Tert-butyl3-[(2-hydroxy-3-methoxy-3-oxopropyl)carbamoyl]azetidine-1-carboxylate(354)

In a similar fashion to general procedure 13, methyl3-amino-2-hydroxypropanoate hydrochloride (2.9 g, 18.64 mmol),1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (4.13 g, 20.5 mmol),TEA (5.45 ml, 39.14 mmol) and DCC (4.04 g, 19.57 mmol) in DCM (80 ml)afforded the title compound (4.47 g, 79%) as a viscous pale yellow oilafter purification by flash column chromatography (eluting with agradient of 0-100% EtOAc/heptane followed by 0-3% MeOH/EtOAc).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=5.92 (s, 1H), 4.32 (dd, J=5.3, 4.3 Hz,1H), 4.14-4.03 (m, 5H), 3.84 (s, 3H), 3.74-3.63 (m, 2H), 3.24-3.14 (m,1H), 1.46 (s, 9H)

HPLCMS (Method M): [m/z]: 325.00 [M+Na]⁺

Methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-4,5-dihydro-1,3-oxazole-5-carboxylate(355)

In a similar fashion to general procedure 14, tert-butyl3-[(2-hydroxy-3-methoxy-3-oxopropyl)carbamoyl]azetidine-1-carboxylate(354) (4.47 g, 14.79 mmol) and DAST (2.15 ml, 16.26 mmol) in DCM (100ml) followed by quenching with K₂COO₃ (4.09 g, 29.57 mmol) afforded thetitle compound (1.61 g, 38%) as a pale yellow oil after purification byflash column chromatography (eluting with a gradient of 20-100%EtOAc/heptane followed by 1% MeOH/EtOAc).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.00 (dd, J=10.8, 6.7 Hz, 1H), 4.27-4.08(m, 5H), 4.00 (ddd, J=14.7, 6.7, 1.0 Hz, 1H), 3.83 (s, 3H), 3.55-3.39(m, 1H), 1.46 (s, 9H)

Methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-5-carboxylate(356)

In a similar fashion to general procedure 16, methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-4,5-dihydro-1,3-oxazole-5-carboxylate(355) (1.61 g, 5.66 mmol), NBS (1.11 g, 6.23 mmol) and AIBN (0.11 g,0.57 mmol) in DCE (60 ml) at 80° C. for 1.5 h gave the title compound(756 mg, 45%) as a pale yellow oil after purification by flash columnchromatography (eluting with a gradient of 0-80% EtOAc/heptane).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.74 (s, 1H), 4.38-4.23 (m, 4H),4.03-3.83 (m, 5H), 1.48 (s, 9H)

HPLCMS (Method M): [m/z]: 304.95 [M+Na]⁺

2-{1-[(Tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-5-carboxylic acid(357)

In a similar fashion to general procedure 5, methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-5-carboxylate(356) (750 mg, 2.66 mmol) and LiOH (382 mg, 15.94 mmol) in THF/water (20ml/20 ml) afforded the title compound (710 mg, 99%) as a pale yellowoil. The title compound was used in the next step without purification.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.83 (s, 1H), 4.40-4.25 (m, 4H),4.04-3.94 (m, 1H), 1.48 (s, 9H)

HPLCMS (Method M): [m/z]: 290.90 [M+Na]⁺

Tert-butyl3-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)azetidine-1-carboxylate(358)

In a similar fashion to general procedure 6,2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-5-carboxylic acid(357) (0.74 g, 2.77 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.61 g, 3.04 mmol), DIPEA (1.59 ml, 9.13 mmol) andHATU (1.16 g, 3.04 mmol) in DCM (30 ml) afforded the title compound(2.26 g, 45% purity) as a pale yellow oil after purification by flashcolumn chromatography (eluting with a gradient of 20-100% EtOAc/heptanefollowed by 2-10% MeOH/EtOAc). The material was used in the next stepwithout further purification.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.44 (dt, J=4.8, 1.3 Hz, 1H), 7.72 (s,1H), 7.60 (s, 1H), 7.53-7.42 (m, 1H), 7.38-7.31 (m, 1H), 4.84 (dd,J=4.8, 1.5 Hz, 2H), 4.42-4.24 (m, 4H), 4.06-3.91 (m, 1H), 1.49 (s, 9H)

HPLCMS (Method M): [m/z]: 377.05 [M+H]⁺

2-(Azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(359)

In a similar fashion to general procedure 2, tert-butyl3-(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)azetidine-1-carboxylate(358) (45%, 2.26 g, 2.7 mmol) and 12M HCl (2 ml) in MeOH (20 ml)afforded the title compound (644 mg, 86%) as a white solid afterfreebasing using an SCX-2 cartridge (10 g), rinsing with DCM and MeOH,then elution with 7N ammonia in MeOH.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.03 (t, J=5.6 Hz, 1H), 8.39 (dt,J=4.5, 1.3 Hz, 1H), 7.74 (s, 1H), 7.70 (ddd, J=10.0, 8.4, 1.2 Hz, 1H),7.41 (dt, J=8.6, 4.4 Hz, 1H), 4.63-4.60 (m, 2H), 4.11-4.02 (m, 1H), 3.85(t, J=7.6 Hz, 2H), 3.78 (t, J=8.2 Hz, 2H)

HPLCMS (Method M): [m/z]: 276.95 [M+H]⁺

2-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(Example Compound No. 2)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(359) (255 mg, 0.92 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (186 mg,0.97 mmol) and DBU (145 μl, 0.97 mmol) in MeCN (10 ml) afforded a crudeintermediate which was further reacted with iron powder (167 mg, 3 mmol)in AcOH (4 ml) to afford the title compound (140 mg, 44%) as a whitesolid after purification by basic prep-HPLC followed by flash columnchromatography (eluting with a gradient of 0-40% MeOH/DCM).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.36 (dt, J=4.7, 1.2 Hz, 1H), 7.69 (s,1H), 7.62 (ddd, J=9.8, 8.4, 1.2 Hz, 1H), 7.52 (s, 2H), 7.41 (dt, J=8.6,4.4 Hz, 1H), 7.24-7.17 (m, 2H), 4.77 (d, J=1.6 Hz, 2H), 3.96-3.87 (m,1H), 3.76 (t, J=7.9 Hz, 2H), 3.58 (t, J=7.3 Hz, 2H), 3.08-3.02 (m, 2H),3.01-2.95 (m, 2H)

HPLCMS (Method B): [m/z]: 421.1 [M+H]⁺

2-{1-[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamideExample Compound No. 3

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(359) (400 mg, 1.45 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G)(335 mg, 1.59 mmol) and DBU (238 μl, 1.59 mmol) in MeCN (10 ml) gave acrude intermediate which was partially purified by flash chromatography(eluting with gradient of 0-20% MeOH/DCM). The intermediate was furtherreacted with iron powder (76 mg) in AcOH (3 ml) to afford the titlecompound (52 mg, 34%) as a beige solid after purification by flashcolumn chromatography (eluting with a gradient of 0-35% MeOH/DCM).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.38-8.34 (m, 1H), 7.69 (s, 1H),7.65-7.60 (m, 1H), 7.44-7.39 (m, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.21-7.15(m, 1H), 6.98-6.92 (m, 1H), 4.77 (d, J=1.6 Hz, 2H), 3.92 (p, J=7.1 Hz,1H), 3.77 (t, J=8.0 Hz, 2H), 3.58 (t, J=7.4 Hz, 2H), 3.08-3.02 (m, 2H),3.02-2.96 (m, 2H)

HPLCMS (Method G): [m/z]: 439.2 [M+H]⁺

2-{1-[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(Example Compound No. 5)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamide(359) (581 mg, 2.1 mmol), N-(5-fluoro-2-nitrophenyl)prop-2-enamide (J)(371 mg, 1.77 mmol) and DBU (346 μl, 2.31 mmol) in MeCN (30 ml) gave acrude intermediate which was further reacted with iron powder (186 mg,3.34 mmol) in AcOH (20 ml) to afford the title compound (205 mg, 56%) asa white solid after purification by basic prep-HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.37 (dt, J=4.6, 1.2 Hz, 1H), 7.69 (s,1H), 7.62 (ddd, J=9.8, 8.4, 1.2 Hz, 1H), 7.51-7.45 (m, 1H), 7.41 (dt,J=8.7, 4.4 Hz, 1H), 7.22 (dd, J=9.1, 2.1 Hz, 1H), 7.03-6.96 (m, 1H),4.77 (d, J=1.6 Hz, 2H), 3.95-3.86 (m, 1H), 3.76 (t, J=8.0 Hz, 2H), 3.57(t, J=7.4 Hz, 2H), 3.06-3.01 (m, 2H), 3.00-2.94 (m, 2H)

HPLCMS (Method B): [m/z]: 439.2 [M+H]⁺

General Scheme 1 Above General Procedure 1: ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (1)

To a suspension of ethyl 3-bromo-2-oxopropanoate (12.35 ml, 107.69 mmol)and tert-butyl (3-amino-3-thioxopropyl) carbamate (20 g, 97.9 mmol) inEtOH (200 ml) was added CaCO₃ (5.3 g, 52.87 mmol) portion wise and thereaction mixture stirred at room temperature for 12 h. The mixture wasconcentrated in vacuo and the residue partitioned between EtOAc (200 ml)and sat. NaHCO₃ (100 ml). The organic layer was separated and washedwith water (100 ml), brine (100 ml), dried (MgSO₄), filtered andconcentrated in vacuo to give the required product. Purification byflash column chromatography (isocratic elution 20% EtOAc/heptane)afforded the title compound (22 g, 69.6%) as a yellow solid.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.29 (s, 1H), 4.39 (q, J=7.1 Hz,2H), 3.47 (t, J=6.5 Hz, 2H), 3.22 (t, J=6.5 Hz, 2H), 1.41 (d, J=6.2 Hz,14H)

HPLCMS (Method A): [m/z]: 301.0 [M+H]⁺

Methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (2)

In a similar fashion to general procedure 1, tert-Butyl(3-amino-3-thioxopropyl)carbamate (10 g, 48.95 mmol), methyl3-bromo-2-oxopropanoate (5.73 ml, 53.85 mmol) and CaCO₃ (0.9 ml, 26.43mmol) in EtOH (120 ml) afforded the title compound (10.2 g, 60%, 83%purity) as a yellow solid after purification by flash chromatography(eluting with a gradient of 20-80% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 286.9 [M+H]⁺

Methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylate(3)

In a similar fashion to general procedure 1, tert-butylN-(2-carbamothioylethyl)carbamate (0.89 g, 4.35 mmol), methyl3-bromo-2-oxobutanoate (0.93 g, 4.78 mmol) and CaCO₃ (0.23 g, 2 mmol) inEtOH (15 ml) afforded the title compound (0.769 g, 58%) as a yellow oilafter purification by flash column chromatography (eluting with agradient of 10-60% EtOAc/heptane).

1H-NMR (CDCl3, 250 MHz): d[ppm]=4.88 (s, 1H), 3.95 (s, 3H), 3.55 (q,J=6.5 Hz, 2H), 3.17 (t, J=6.5 Hz, 2H), 2.76 (s, 3H), 1.46 (s, 9H)

HPLCMS (Method A): [m/z]: 301.05 [M+H]⁺

Ethyl2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylate(4)

In a similar fashion to general procedure 1, tert-butylN-(3-carbamothioylpropyl)carbamate (535 mg, 2.45 mmol), ethyl3-bromo-2-oxopropanoate (0.31 ml, 2.7 mmol) and CaCO₃ (132 mg, 1.32mmol) in EtOH (10 ml) afforded the title compound (726 mg, 93%) as ayellow oil after purification by flash column chromatography (elutingwith a gradient of 0-50% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.38 (s, 1H), 6.90 (s, 1H), 4.29 (q,J=7.1 Hz, 2H), 3.15-2.90 (m, 4H), 1.83 (m, 2H), 1.38 (s, 9H), 1.30 (t,J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 315 [M+H]⁺

General Procedure 2: Methyl 2-(2-aminoethyl)-1,3-thiazole-4-carboxylate(5)

4M HCl in dioxane (44 ml, 176 mmol) was added to a solution of methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (2)(10.2 g, 35.62 mmol) in dioxane and the mixture was stirred at roomtemperature for 12 h, then at 40° C. for 24 h. The mixture was cooled toroom temperature and evaporated in vacuo. The residue was dissolved inDCM (20 ml) and washed with saturated NaHCO₃ (3×10 ml). The combinedaqueous phases were re-extracted with diethyl ether (3×100 ml) and thecombined organic phases were dried (MgSO₄), filtered and evaporated invacuo to afford the title compound (1.96 g, 30%) as a brown solid.

HPLCMS (Method A): [m/z]: 186.9 [M+H]⁺

General Procedure 3: Methyl2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylate(6)

A suspension of methyl 2-(2-aminoethyl)-1,3-thiazole-4-carboxylate (5)(1.96 g, 10.52 mmol), 1H-benzimidazole-2-carbaldehyde (2.31 g, 15.79mmol) and DIPEA (1.83 ml, 10.52 mmol) in MeOH (100 ml) was stirred atroom temperature for 12 h. The reaction mixture was cooled to 0° C.,NaBH₄ (0.597 g, 15.79 mmol) was added and the mixture stirred at roomtemperature for 2 h. The reaction mixture was concentrated in vacuo andthe residue dissolved in EtOAc (100 ml) and washed with saturated Na₂CO₃(2×50 ml). The combined aqueous layers were extracted with EtOAc (3×50ml) and the combined organic layers dried (MgSO₄), filtered andevaporated in vacuo. Purification by flash column chromatography (KP—NH,eluting with a gradient of 0-10% MeOH/DCM) afforded the title compound(1.4 g, 38%, 90% purity) as a tan solid.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.27 (s, 1H), 7.60-7.49 (m, 2H),7.29-7.17 (m, 2H), 4.09 (s, 2H), 3.92 (s, 3H), 3.26 (t, J=6.3 Hz, 2H),3.10 (t, J=6.8 Hz, 2H)

HPLCMS (Method A): [m/z]: 317 [M+H]⁺

General Procedure 4 Tert-butyl2-({[(tert-butoxy)carbonyl]({2-[4-(methoxycarbonyl)-1,3-thiazol-2-yl]ethyl})amino}methyl)-1H-1,3-benzodiazole-1-carboxylate(7)

To a solution of methyl2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylate(6) (74%, 2.94 g, 6.88 mmol), Boc₂O (3.75 g, 17.19 mmol) and TEA (2.38ml, 17.19 mmol) in THF (60 ml) was added DMAP (168 mg, 1.38 mmol) andthe reaction was stirred at room temperature for 16 h. The reaction wasevaporated to dryness, diluted with EtOAc (100 ml) and washed with water(3×50 ml). The organic was dried over MgSO₄, filtered and evaporated todryness. The crude residue was purified by FCC eluting with 0-100% EtOAcin heptane to give 3.8 g of desired product.

General Procedure 5:2-(2-{[(Tert-butoxy)carbonyl]({1-[(tert-butoxy)carbonyl]-1H-1,3-benzodiazol-2-yl}methyl)amino}ethyl)-1,3-thiazole-4-carboxylicacid (8)

Lithium hydroxide (0.48 mg, 20.08 mmol) was added to a solution oftert-butyl2-({[(tert-butoxy)carbonyl]({2-[4-(methoxycarbonyl)-1,3-thiazol-2-yl]ethyl})amino}methyl)-1H-1,3-benzodiazole-1-carboxylate(7) (3.8 g, 6.69 mmol) in THF/water (40 ml/10 ml) at 0° C. The reactionmixture was stirred at room temperature for 48 h. The mixture wasconcentrated in vacuo and acidified to pH 3-4 using AcOH. The reactionmixture was extracted with THF/EtOAc (3:1, 3×50 ml). The combinedorganic extracts were washed with brine (100 ml), dried (MgSO₄),filtered, reduced in vacuo and azeotroped with heptane (3×50 ml) to givethe title compound (2.4 g, 84.6%) as a yellow foam.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.15 (d, J=17.0 Hz, 1H), 7.69 (s,2H), 7.27 (dd, J=6.1, 3.2 Hz, 2H), 4.79 (s, 2H), 3.87-3.74 (m, 2H),3.40-3.33 (m, 3H), 1.38-1.01 (m, 1 OH)

HPLCMS (Method A): [m/z]: 403 [M+H]⁺

General Procedure 6: Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethylcarbamate(9)

To a stirring solution of2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (3 g, 7.08 mmol), 1-(pyridin-2-yl)methanamine (1.1 ml, 10.62mmol), DIPEA (3.7 ml, 21.24 mmol) and DMF (50 ml) at room temperaturewas added HATU (5.39 g, 14.16 mmol). The reaction mixture was allowed tostir at room temperature for 16 h. The reaction was diluted with EtOAc(100 ml) and washed with sat. NaHCO₃ (3×50 ml) and brine (3×50 ml). Theorganic layer was separated, dried (MgSO4), filtered and evaporated todryness. The crude residue was purified by flash column chromatography(kp-NH, eluting with a gradient of 20-100% EtOAc in heptane) and thenazeotroped with heptane to give the title compound (2.2 g, 62%) as ayellow foam.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.49 (d, J=4.4 Hz, 1H), 8.10 (s, 1H),7.80 (td, J=7.8, 1.7 Hz, 1H), 7.54 (s, 2H), 7.42 (d, J=7.9 Hz, 1H), 7.31(dd, J=7.1, 5.2 Hz, 1H), 7.26-7.20 (m, 2H), 4.75 (d, J=12.3 Hz, 2H),4.70 (s, 2H), 3.92-3.79 (m, 2H), 3.36 (d, J=8.1 Hz, 1H), 1.43-1.25 (m,10H)

HPLCMS (Method D): [m/z]: 493.1 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(cyclohexylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(10)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), cyclohexylmethanamine (33.69 mg, 0.298mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) inDMF (4 ml) at room temperature for 1 h afforded the title compound (116mg, 47% purity) as an off white oil after purification by flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM). The titlecompound was used in the next step without further purification.

HPLCMS (Method H): [m/z]: 498.7 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-1,3-thiazol-2-yl]ethyl}carbamate(11)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), 1,2,3,4-tetrahydroisoquinoline (39.64mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298mmol) in DMF (4 ml) at room temperature for 1 h afforded the titlecompound (124 mg, 59% purity) as an off white oil after purification byflash column chromatography (eluting with a gradient of 0-10% MeOH/DCM).The title compound was used in the next step without furtherpurification.

HPLCMS (Method H): [m/z]: 518.7 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(thiophen-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(12)

To a solution of2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.373 mmol) in DMF (10 ml) was added1H-1,2,3-benzotriazol-1-ol (50 mg, 0.373 mmol) and EDC:HCl (71 mg, 0.373mmol) at 0° C. The reaction mixture was allowed to stir for 15 minbefore TEA (38 mg, 0.373 mmol) was added followed bythiophen-2-ylmethanamine (42 mg, 0.373 mmol). The reaction mixture wasallowed to warm up to room temperature and stir overnight. The titlecompound (185 mg, 16% purity) was obtained after work up followinggeneral procedure 6. This was used in the next step withoutpurification.

HPLCMS (Method H): [m/z]: 498.6 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[benzyl(methyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(13)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), benzyl(methyl)amine (36.06 mg, 0.298mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) inDMF (4 ml) at room temperature for 1 h afforded the title compound (118mg, 55% purity) as an off white oil after purification by flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM). The titlecompound was used in the next step without further purification.

HPLCMS (Method H): [m/z]: 506.7 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(morpholine-4-carbonyl)-1,3-thiazol-2-yl]ethyl}carbamate(14)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), morpholine (25.93 mg, 0.298 mmol), DIPEA(96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) in DMF (4 ml) atroom temperature for 1 h afforded the title compound (110 mg) as an offwhite oil after purification by flash column chromatography (elutingwith a gradient of 0-10% MeOH/DCM). The title compound was used in thenext step without further purification.

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[methyl(phenyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(15)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), N-methylaniline (31.89 mg, 0.298 mmol),DIPEA (96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) in DMF (4ml) at room temperature for 1 h afforded the title compound (118 mg, 59%purity) as an off white oil after purification by flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM). The titlecompound was used in the next step without further purification.

HPLCMS (Method H): [m/z]: 492.7 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(pyrrolidin-1-yl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(16)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (200 mg, 0.497 mmol), [3-(pyrrolidin-1-yl)phenyl]methanamine(105 mg, 0.596 mmol), DIPEA (193 mg, 1.491 mmol) and HATU (227 mg, 0.596mmol) in DMF (5 ml) at room temperature for 1 h afforded the titlecompound (100 mg, 30%, 84% purity) as an off white oil afterpurification by flash column chromatography (eluting with a gradient of0-10% MeOH/DCM).

HPLCMS (Method H): [m/z]: 561.7 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(dimethylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(17)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.248 mmol), dimethylamine (2 M solution in THF) (13mg, 0.298 mmol), DIPEA (96 mg, 0.745 mmol) and HATU (113 mg, 0.298 mmol)in DMF (10 ml) at room temperature for 1 h afforded the title compound(90 mg, 67%, 80% purity) as a white solid after purification by flashcolumn chromatography (eluting with a gradient of 0-10% MeOH/DCM).

HPLCMS (Method H): [m/z]: 430.6 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[cyclohexyl(propan-2-yl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(18)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), N-(propan-2-yl)cyclohexanamine (42.04mg, 0.298 mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298mmol) in DMF (4 ml) at room temperature for 1 h afforded the titlecompound (124 mg, 17% purity) as an off white oil after purification byflash column chromatography (eluting with a gradient of 0-10% MeOH/DCM).The title compound was used in the next step without furtherpurification.

HPLCMS (Method H): [m/z]: 526.8 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(2-phenylpropan-2-yl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(19)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), 2-phenylpropan-2-amine (40.24 mg, 0.298mmol), DIPEA (96.16 mg, 0.744 mmol) and HATU (113.16 mg, 0.298 mmol) inDMF (4 ml) at room temperature for 1 h afforded the title compound (120mg, 51% purity) as an off white oil after purification by flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM). The titlecompound was used in the next step without further purification.

HPLCMS (Method H): [m/z]: 520.7 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(20)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (350 mg, 0.87 mmol), phenylmethanamine (103 mg, 0.957 mmol),DIPEA (337 mg, 2.61 mmol) and HATU (397 mg, 1.04 mmol) in DMF (10 ml)afforded the title compound (390 mg, 89% purity) as a white solid afterpurification by flash column chromatography (eluting with a gradient of0-10% MeOH/DCM).

HPLCMS (Method H): [m/z]: 492.6 [M+H]⁺

Tert-butylN-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}-N-[(1-methyl-1H-1,3-benzodiazol-2-yl)methyl]arbamate(21

To a stirred solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(20) (380 mg, 0.773 mmol) and TEA (78 mg, 0.773 mmol) in DCM (15 ml) wasadded MeI (165 mg, 1.159 mmol) under argon atmosphere. The reactionmixture was stirred at room temperature overnight. The reaction mixturewas evaporated under vacuum to dryness to afford the title compound (280mg, 72% purity) as an off white solid. The crude product was used in thenext step without purification.

HPLCMS (Method H): [m/z]: 506.6 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(22)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (199.6 mg, 0.496 mmol), pyridin-3-ylmethanamine (59 mg, 0.546mmol), DIPEA (192.3 mg, 1.488 mmol) and HATU (226 mg, 0.595 mmol) in DMF(8 ml) afforded the title compound (184 mg, 75%) as a white solid afterpurification by flash column chromatography (eluting with a gradient of0-10% MeOH/DCM).

1H-NMR (CDCl₃, 400 MHz): d[ppm]=8.61 (d, J=1.6 Hz, 1H), 8.52 (d, J=3.6Hz, 1H), 7.96 (s, 1H), 7.81 (s, 1H), 7.73-7.67 (m, 1H), 7.55 (dd, J=6.0,3.2 Hz, 2H), 7.28 (s, 1H), 7.25 (dd, J=6.1, 3.2 Hz, 2H), 4.63 (d, J=6.6Hz, 4H), 3.77 (t, J=6.5 Hz, 2H), 3.22 (t, J=6.3 Hz, 2H), 1.37 (s, 9H)

HPLCMS (Method H): [m/z]: 493.4 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-4-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(23)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (199.6 mg, 0.496 mmol), pyridin-4-ylmethanamine (59 mg, 0.546mmol), DIPEA (192.3 mg, 1.488 mmol) and HATU (226 mg, 0.595 mmol) in DMF(8 ml) afforded the title compound (140 mg, 57%) as a white solid afterpurification by flash column chromatography (eluting with a gradient of0-10% MeOH/DCM).

1H-NMR (CDCl₃, 400 MHz): d[ppm]=8.56 (d, J=5.9 Hz, 2H), 7.98 (s, 1H),7.82 (s, 1H), 7.59-7.48 (m, 2H), 7.24 (dd, J=6.0, 3.2 Hz, 4H), 4.62 (d,J=6.6 Hz, 4H), 3.78 (t, J=6.5 Hz, 2H), 3.25 (t, J=6.4 Hz, 2H), 1.41 (d,J=13.9 Hz, 9H)

HPLCMS (Method H): [m/z]: 493.4 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(24)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (80.09 mg, 0.199 mmol),[3-(trifluoromethyl)pyridin-2-yl]methanamine hydrochloride (46.54 mg,0.219 mmol), DIPEA (102.9 mg, 0.796 mmol) and HATU (90.8 mg, 0.239 mmol)in DMF (2.5 ml) afforded the title compound (85 mg, 76%, 98% purity) asa white solid after purification by flash column chromatography (elutingwith a gradient of 0-10% MeOH/DCM).

HPLCMS (Method H): [m/z]: 561.5 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(5,6,7,8-tetrahydroquinolin-8-yl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(25)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (80.09 mg, 0.199 mmol),N-methyl-5,6,7,8-tetrahydroquinolin-8-amine dihydrochloride (48.4 mg,0.219 mmol), DIPEA (102.9 mg, 0.796 mmol) and HATU (90.8 mg, 0.239 mmol)in DMF (2.5 ml) afforded the title compound (92 mg, 87%) as a whitesolid after purification by flash column chromatography (eluting with agradient of 0-10% MeOH/DCM).

HPLCMS (Method H): [m/z]: 533.5 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(26)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (80.9 mg, 0.199 mmol),N-methyl-5H,6H,7H-cyclopenta[b]pyridin-7-amine hydrochloride (37.35 mg,0.219 mmol), DIPEA (102.9 mg, 0.796 mmol) and HATU (90.8 mg, 0.239 mmol)in DMF (2.5 ml) afforded the title compound (90 mg, 87%) as a whitesolid after purification by flash column chromatography (eluting with agradient of 0-10% MeOH/DCM).

HPLCMS (Method H): [m/z]: 519.5 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylmorpholin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(27)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (3 g, 7.545 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (2.26 g, 11.18 mmol), DIPEA (12.98 ml, 74.54 mmol)and HATU (4.251 g, 11.18 mmol) in DMF (60 ml) afforded the titlecompound (4.13 mg, 89%) as a yellow oil after purification by flashcolumn chromatography (kp-NH, eluting with a gradient of 20-100%EtOAc/heptane followed by 0-20% MeOH/EtOAc).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.29 (s, 1H), 8.69 (s, 1H), 8.36 (s,1H), 8.17 (s, 1H), 7.70 (t, J=9.5 Hz, 1H), 7.48 (s, 2H), 7.40 (dt,J=8.6, 4.4 Hz, 1H), 7.14 (s, 2H), 4.66 (d, J=8.8 Hz, 4H), 3.73 (s, 2H),2.52 (s, 2H), 1.99 (s, 4H), 1.26 (d, J=44.9 Hz, 9H)

HPLCMS (Method A): [m/z]: 511.15 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylmorpholin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(28)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), (4-methylmorpholin-3-yl)methanamine(35.5 mg, 0.273 mmol), DIPEA (96.16 mg, 0.744 mmol) and T3P (189.4 mg,0.298 mmol) in DMF (4 ml) afforded the title compound (90 mg, 70%) as awhite solid after purification by flash column chromatography (elutingwith a gradient of 0-10% MeOH/DCM).

1H-NMR (CDCl₃, 400 MHz): d[ppm]=7.90 (s, 1H), 7.59 (s, 3H), 7.28 (t,J=3.6 Hz, 1H), 4.64 (s, 2H), 3.79 (td, J=12.0, 4.7 Hz, 5H), 3.70-3.59(m, 2H), 3.47 (ddd, J=14.7, 10.3, 6.6 Hz, 4H), 3.22 (t, J=6.4 Hz, 2H),2.74 (d, J=11.4 Hz, 1H), 2.49-2.32 (m, 6H), 1.40 (s, 9H)

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(29)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid 6 (99.8 mg, 0.248 mmol), (6-methylpyridin-2-yl)methanamine (33.33mg, 0.273 mmol), DIPEA (96.16 mg, 0.744 mmol) and T3P (189.4 mg, 0.298mmol) in DMF (4 ml) afforded the title compound (95 mg, 75%) as a whitesolid after purification by flash column chromatography (eluting with agradient of 0-10% MeOH/DCM).

1H-NMR (CDCl₃, 400 MHz): d[ppm]=8.14 (s, 1H), 7.90 (s, 1H), 7.55 (dd,J=14.1, 6.6 Hz, 3H), 7.23 (dd, J=6.0, 3.2 Hz, 2H), 7.14 (d, J=7.7 Hz,1H), 7.06 (d, J=7.7 Hz, 1H), 4.71 (d, J=5.5 Hz, 2H), 4.66 (s, 2H), 3.80(t, J=6.3 Hz, 2H), 3.22 (t, J=6.4 Hz, 2H), 2.55 (s, 3H), 1.34 (s, 9H)

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(30)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (99.8 mg, 0.248 mmol), (5-fluoropyridin-2-yl)methanamine (34.41mg, 0.273 mmol), DIPEA (96.16 mg, 0.744 mmol) and T3P (189.4 mg, 0.298mmol) in DMF (4 ml) afforded the title compound (89 mg, 70%) as a whitesolid after purification by flash column chromatography (eluting with agradient of 0-10% MeOH/DCM).

1H-NMR (CDCl₃, 400 MHz): d[ppm]=8.44 (s, 1H), 8.12 (s, 1H), 7.92 (s,1H), 7.56 (s, 2H), 7.44-7.30 (m, 2H), 7.25 (dd, J=6.1, 3.2 Hz, 2H), 4.73(d, J=5.6 Hz, 2H), 4.66 (s, 2H), 3.79 (t, J=6.3 Hz, 2H), 3.23 (t, J=6.3Hz, 2H), 3.04 (s, 1H), 1.34 (s, 9H)

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrimidin-4-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(31)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.373 mmol), pyrimidin-4-ylmethanamine (48.8 mg, 0.447mmol), DIPEA (48.1 mg, 0.373 mmol) and HATU (141.7 mg, 0.373 mmol) inDMF (2 ml) at room temperature overnight gave the title compound (80 mg,60% purity) as an yellow oil after purification by flash columnchromatography (eluting with a gradient of 10% MeOH in DCM).

HPLCMS (Method H): [m/z]: 494.6 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methoxypyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(32)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.373 mmol), (5-methoxypyridin-2-yl)methanamine (48.17mg, 0.447 mmol), DIPEA (48.1 mg, 0.373 mmol) and HATU (141.7 mg, 0.373mmol) in DMF (2 ml) at room temperature overnight gave the titlecompound (80 mg, 41%) as brown solid after purification by flash columnchromatography (eluting with a gradient of 10% MeOH in DCM).

HPLCMS (Method H): [m/z]: 523.6 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrazin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(33)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.373 mmol), pyrazin-2-ylmethanamine (48.8 mg, 0.447mmol), DIPEA (192.68 mg, 1.491 mmol) and HATU (141.7 mg, 0.373 mmol) inDMF (2 ml) at room temperature overnight gave the title compound (95 mg,52%) as yellow solid after purification by flash column chromatography(eluting with a gradient of 10% MeOH in DCM).

HPLCMS (Method H): [m/z]: 394.5 [M+H-Boc]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-oxo-1,6-dihydropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(34)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.373 mmol), 6-(aminomethyl)-1,2-dihydropyridin-2-one(55.52 mg, 0.447 mmol), DIPEA (48.17 mg, 0.373 mmol) and HATU (141.7 mg,0.373 mmol) in DMF (2 ml) at room temperature overnight gave the titlecompound (90 mg, 47%) as yellow solid after purification by flash columnchromatography (eluting with a gradient of 10% MeOH/DCM).

HPLCMS (Method H): [m/z]: 509.6 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-carbamoylpyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(35) and Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-cyanopyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(36)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.248 mmol), 5-(aminomethyl)pyridine-2-carbonitrile(33 mg, 0.248 mmol), HATU (189 mg, 0.497 mmol) and DIPEA (96 mg, 0.745mmol) in DMF (1 ml) at room temperature for 18 h, gave a 2:1 ratio ofboc amide and boc nitrile (80 mg) after purification by flash columnchromatography (DCM:MeOH, 9:1). The mixture was used in the next stepwithout separation.

HPLCMS (Method H): [m/z]: 418.5 [M+H-boc]⁺ and 436.3 [M+H-boc]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3,5-dimethylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(37)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (0.3 g, 0.708 mmol), (3,5-dimethylpyridin-2-yl)methanaminehydrochloride (0.183 g, 1.062 mmol), DIPEA (0.555 ml, 3.187 mmol) andHATU (0.404 g, 1.062 mmol) in DMF (6 ml) at room temperature for 4 h,gave the title compound (0.198 g, 51%) as a yellow oil afterpurification by flash column chromatography (kp-NH, eluting with agradient of EtOAc (30%)/heptane (70%) followed by 100% EtOAc).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.29 (s, 1H), 8.75 (s, 1H), 8.19 (s,2H), 7.56 (d, J=7.6 Hz, 1H), 7.48-7.40 (m, 2H), 7.14 (p, J=7.0 Hz, 2H),4.66 (s, 2H), 4.53 (d, J=4.8 Hz, 2H), 3.73 (s, 2H), 2.27 (s, 3H), 2.23(s, 3H), 1.31 (s, 9H)

HPLCMS (Method A): [m/z]: 521.15 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(38)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.20 mmol), 1-(pyrimidin-2-yl)methanamine (22 mg, 0.20mmol), DIPEA (0.1 ml, 0.60 mmol) and HATU (113 mg, 0.30 mmol) in DCM (5ml) afforded the title compound (86 mg, 73%) as a brown residue afterpurification by flash column chromatography (eluting with a gradient of0-20% MeOH/EtOAc).

HPLCMS (Method A): [m/z]: 494.1 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(4-methylpiperazin-1-yl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(39)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (130 mg, 0.24 mmol, 75% purity),1-[2-(4-methylpiperazin-1-yl)phenyl]methanamine (75 mg, 0.36 mmol),DIPEA (127 μl, 0.73 mmol) and HATU (138 mg, 0.36 mmol) in DMF (2 ml)afforded the title compound (13 mg, 9%) as a white solid followingpurification by basic prep-HPLC.

HPLCMS (Method D): [m/z]: 590.3 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2,6-difluorophenyl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(40)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (110 mg, 0.25 mmol, 90% purity),1-(2,6-difluorophenyl)methanamine (53 mg, 0.37 mmol), DIPEA (0.13 ml,0.74 mmol) and HATU (140 mg, 0.37 mmol) in DMF (2 ml) afforded the titlecompound (90 mg, 68%) as a yellow oil after purification by flash columnchromatography (kp-NH, eluting with a gradient of 2-100% EtOAc/heptane).

HPLCMS (Method E): [m/z]: 528.3 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(dimethylamino)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(41)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (109 mg, 0.22 mmol, 80% purity),2-(aminomethyl)-N,N-dimethylaniline (66 mg, 0.44 mmol), DIPEA (226 μl,1.30 mmol) and HATU (240 mg, 0.64 mmol) in DMF (2 ml) at 50° C. affordedthe title compound (73 mg, 61%) as an orange oil after purification byflash column chromatography (kp-NH, eluting with a gradient of 5-100%EtOAc/heptane).

HPLCMS (Method D): [m/z]: 535.2 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-cyanophenyl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(42)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (109 mg, 0.22 mmol, 80% purity), 2-(aminomethyl)benzonitrilehydrochloride (74 mg, 0.44 mmol), DIPEA (226 μl, 1.30 mmol) and HATU(240 mg, 0.64 mmol) in DMF (2 ml) at 50° C. afforded the crude titlecompound (54 mg, 30%, 63% purity) as an orange oil after purification byflash column chromatography (kp-NH, eluting with a gradient of 5-100%EtOAc/heptane).

HPLCMS (Method D): [m/z]: 517.2 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(trifluoromethoxy)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(43)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (109 mg, 0.22 mmol, 80% purity),1-[2-(trifluoromethoxy)phenyl]methanamine (103 mg, 0.54 mmol), DIPEA(283 μl, 1.63 mmol) and HATU (248 mg, 0.65 mmol) in DMF (2 ml) at 50° C.afforded the crude title compound (110 mg, 78%, 88% purity) as a yellowoil after purification by flash column chromatography (kp-NH, elutingwith a gradient of 8-100% EtOAc/heptane).

HPLCMS (Method E): [m/z]: 576.2 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1-phenylethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(44)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (0.11 g, 0.22 mmol, 80% purity), 1-phenylethanamine (0.07 ml,0.54 mmol), DIPEA (0.303 ml, 1.63 mmol) and HATU (0.25 g, 0.64 mmol) inDMF (2 ml) afforded the crude title compound (110 mg, 77%, 77% purity)as a yellow oil after purification by flash column chromatography(KP—NH, eluting with a gradient of 8-100% EtOAc/heptane).

HPLCMS (Method E): [m/z]: 506.2 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(difluoromethoxy)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(45)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (109 mg, 0.22 mmol, 80% purity),1-[2-(difluoromethoxy)phenyl]methanamine (83 mg, 0.48 mmol), DIPEA (0.23ml, 1.3 mmol) and HATU (250 mg, 0.65 mmol) in DMF (2 ml) afforded thecrude title compound (470 mg) as an orange oil which was used in thenext step without purification.

HPLCMS (Method A): [m/z]: 558.25 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(morpholine-4-sulfonyl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(46)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (109 mg, 0.217 mmol, 80% purity),1-[2-(morpholin-4-ylsulfonyl)phenyl]methanamine hydrochloride (140 mg,0.48 mmol), DIPEA (0.23 ml, 1.3 mmol) and HATU (247 mg, 0.65 mmol) inDMF (2 ml) afforded the crude title compound (440 mg) as an orange oilafter direct evaporation of the reaction mixture in vacuo. The materialwas used without purification.

HPLCMS (Method A): [m/z]: 641.35 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[2-(pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(47)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.2 mmol, 80% purity), 2-(pyridin-2-yl)ethanamine (49mg, 0.4 mmol), DIPEA (104 μl, 0.6 mmol) and HATU (151 mg, 0.4 mmol) inDMF (2 ml) afforded the title compound (52 mg, 52%) as a cream solidafter purification by flash column chromatography KP—NH, eluting with agradient of 5-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 507.15 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(3-fluoropyridin-2-yl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(48)

In a similar fashion to general procedure 6, a solution of2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (80%, 150 mg, 0.3 mmol), 3-fluoropyridin-2-amine (100 mg, 0.89mmol), DIPEA (312 μl, 1.78 mmol) and HATU (340 mg, 0.87 mmol) in DMF (2ml) was heated at 100° C. for 16 h. The reaction mixture wasconcentrated in vacuo to give the crude title compound (705 mg) as abrown oil which was used in the next step without purification.

HPLCMS (Method A): [m/z]: 497.10 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(2-phenylethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(49)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (0.1 g, 0.25 mmol), 2-phenylethanamine (0.03 ml, 0.25 mmol),DIPEA (0.13 ml, 0.75 mmol) and HATU (0.14 g, 0.37 mmol) in DMF (2 ml)afforded the title compound (71 mg, 56%) as a yellow oil afterpurification by flash column chromatography (eluting with a gradient of2-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 506.2 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoro-6-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(50)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.298 mmol, 80% purity),(3-fluoro-6-methylpyridin-2-yl)methanamine hydrochloride (79 mg, 0.447mmol), DIPEA (156 μl, 0.894 mmol) and HATU (230 mg, 0.596 mmol) in DMF(3 ml) afforded the title compound (76 mg, 48%) as a pale yellow oilafter purification by flash column chromatography (kp-NH, eluting with agradient of 0-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 525.40 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[1-(pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(51)

In a similar manner to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.298 mmol, 80% purity), 1-(pyridin-2-yl)ethanamine(55 mg, 0.447 mmol), DIPEA (156 μl, 0.894 mmol) and HATU (227 mg, 0.596mmol) in DMF (3 ml) afforded the title compound (78 mg, 50%) as acolourless oil after purification by flash column chromatography (kp-NH,eluting with a gradient of 0-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 507.20 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[6-(trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(52)

In a similar manner to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.298 mmol, 80% purity),1-[6-(trifluoromethyl)pyridin-3-yl]methanamine (79 mg, 0.447 mmol),DIPEA (156 μl, 0.894 mmol) and HATU (227 mg, 0.596 mmol) in DMF (3 ml)afforded the title compound (92 mg, 46%) as a colourless oil afterpurification by flash column chromatography (kp-NH, eluting with agradient of 0-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 561.35 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(53)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.34 mmol, 92% purity),1-(3-chloropyridin-2-yl)methanamine dihydrochloride (111 mg, 0.51 mmol),DIPEA (299 μl, 1.71 mmol) and HATU (196 mg, 0.51 mmol) in DMF (2 ml)afforded the title compound (161 mg, 73% purity, 63%) as a yellow oilafter purification by flash column chromatography (kp-NH, eluting with agradient of 20-100% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=10.47 (s, 1H), 8.59 (s, 1H), 8.52-8.42(m, 1H), 7.92 (s, 1H), 7.71 (d, J=8.2 Hz, 2H), 7.32 (s, 1H), 7.25-7.16(m, 3H), 4.85 (d, J=4.8 Hz, 2H), 4.69 (s, 2H), 3.81 (s, 2H), 3.23 (t,J=6.5 Hz, 2H), 1.35 (s, 9H)

HPLCMS (Method A): [m/z]: 527.35 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(tert-butoxy)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(54)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.34 mmol, 92% purity),1-(2-tert-butoxypyridin-3-yl)methanamine (93 mg, 0.514 mmol), DIPEA (179μl, 1.03 mmol) and HATU (196 mg, 0.51 mmol) in DMF (2 ml) afforded thetitle compound (205 mg, 61%, 58% purity) as a yellow oil afterpurification by flash column chromatography (kp-NH, eluting with agradient of 20-100% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=10.09 (s, 1H), 7.89 (d, J=15.7 Hz, 2H),7.71 (s, 1H), 7.54-7.45 (m, 2H), 7.40 (d, J=4.9 Hz, 1H), 7.24 (s, 1H),6.77 (td, J=7.3, 5.0 Hz, 2H), 4.60 (s, 2H), 4.49 (d, J=6.5 Hz, 2H), 3.77(t, J=6.5 Hz, 2H), 3.22 (s, 2H), 1.63 (s, 9H), 1.33 (s, 9H)

HPLCMS (Method A): [m/z]: 565.15 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-imidazol-5-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(55)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.37 mmol), (1-methyl-1H-imidazol-5-yl)methanamine (62mg, 0.56 mmol), DIPEA (185 μl, 1.12 mmol) and HATU (213 mg, 0.56 mmol)in DMF (2 ml) afforded the title compound (175 mg, 95%) as a yellow oilafter purification by flash column chromatography (eluting with agradient of 0-3% MeOH/DCM).

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.08 (s, 1H), 7.58-7.52 (m, 3H),7.26-7.20 (m, 2H), 6.96 (s, 1H), 4.69 (d, J=12.4 Hz, 2H), 4.60 (s, 2H),3.95-3.75 (m, 2H), 3.70 (s, 3H), 3.39-3.24 (m, 2H), 1.44-1.26 (m, 9H)

HPLCMS (Method A): [m/z]: 496.05 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1,3-oxazol-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(56)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.298 mmol, 80% purity), 1,3-oxazol-2-ylmethanaminedihydrochloride (102 mg, 0.596 mmol), DIPEA (312 μl, 1.79 mmol) and HATU(227 mg, 0.596 mmol) in DMF (3 ml) afforded the title compound (94 mg,63%) as a tan oil after purification by flash column chromatography(kp-NH, eluting with a gradient of 0-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 483.05 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(57)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (150 mg, 0.298 mmol, 80% purity),1-(1-methyl-1H-pyrazol-3-yl)methanamine (50 mg, 0.45 mmol), DIPEA (156μl, 0.894 mmol) and HATU (227 mg, 0.596 mmol) in DMF (3 ml) afforded thetitle compound (53 mg, 34%) as a tan oil after purification by flashcolumn chromatography (kp-NH, eluting with a gradient of 0-100%EtOAc/heptane).

HPLCMS (Method A): [m/z]: 496.45 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(58)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.23 mmol, 92% purity), 1-(pyridazin-3-yl)methanamine(37 mg, 0.34 mmol), DIPEA (119 μl, 0.69 mmol) and HATU (130 mg, 0.34mmol) in DMF (2 ml) afforded the title compound (101 mg, 88%) as a paleyellow oil after purification by flash column chromatography (kp-NH,eluting with a gradient of 50-100% EtOAc/heptane followed by 0-15%MeOH/EtOAc).

HPLCMS (Method A): [m/z]: 494.1 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-5-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(59)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.23 mmol, 92% purity),1-(1-methyl-1H-pyrazol-5-yl)methanamine (38 mg, 0.34 mmol), DIPEA (119μl, 0.69 mmol) and HATU (130 mg, 0.34 mmol) in DMF (2 ml) afforded thetitle compound (51 mg, 45%) as a pale yellow oil after purification byflash column chromatography (kp-NH, eluting with a gradient of 50-100%EtOAc/heptane followed by 0-20% MeOH/EtOAc).

HPLCMS (Method A): [m/z]: 496.3 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoropyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(60)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.23 mmol, 92% purity),1-(3-fluoropyridin-4-yl)methanamine (43 mg, 0.34 mmol), DIPEA (119 μl,0.69 mmol) and HATU (130 mg, 0.34 mmol) in DMF (3 ml) afforded the titlecompound (137 mg, 83%, 71% purity) as a yellow oil after flash columnchromatography (kp-NH, eluting with a gradient of 50-100%EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=10.10 (s, 1H), 8.43 (d, J=6.0 Hz, 1H),8.37 (dd, J=9.8, 4.9 Hz, 2H), 7.96 (s, 1H), 7.81-7.68 (m, 2H), 7.40 (d,J=8.6 Hz, 1H), 7.35-7.27 (m, 1H), 7.25-7.22 (m, 1H), 4.68 (d, J=6.0 Hz,2H), 4.62 (s, 2H), 3.78 (t, J=6.5 Hz, 2H), 3.27-3.23 (m, 2H), 1.37 (s,9H)

HPLCMS (Method A): [m/z]: 511.15 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-methylpyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(61)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (700 mg, 1.65 mmol, 95% purity),(3-methylpyridin-4-yl)methanamine dihydrochloride (387 mg, 1.98 mmol),DIPEA (863 μl, 4.9 mmol) and HATU (1260 mg, 3.3 mmol) in DMF (10 ml)afforded the title compound (363 mg, 43%) as a yellow oil afterpurification by flash chromatography (kp-NH, using an elution gradient20-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 507.1 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(62)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.25 mmol), (1-methyl-1H-pyrazol-4-yl)methanamine (41mg, 0.37 mmol), DIPEA (130 μl, 0.75 mmol) and HATU (142 mg, 0.37 mmol)in DMF (2 ml) afforded the title compound (125 mg, quant.) as a yellowoil after purification by flash column chromatography (eluting with agradient of 0-20% MeOH/EtOAc).

HPLCMS (Method A): [m/z]: 496.1 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methylpyridazin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(63)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.23 mmol, 92% purity),(6-methylpyridazin-3-yl)methanamine (42 mg, 0.34 mmol), DIPEA (119 μl,0.69 mmol) and HATU (130 mg, 0.34 mmol) in DMF (3 ml) afforded the crudetitle compound (99 mg, 67%, 79% purity) after flash columnchromatography (kp-NH, eluting with a gradient of 70-100%EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=10.50 (s, 1H), 8.28 (s, 1H), 7.92 (s,1H), 7.72 (s, 1H), 7.40-7.29 (m, 3H), 7.23 (dd, J=6.4, 2.8 Hz, 2H), 4.68(s, 2H), 3.82 (s, 2H), 3.24 (s, 2H), 2.73 (s, 2H), 2.71 (s, 3H), 1.36(s, 9H)

HPLCMS (Method A): [m/z]: 508.10 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1H-imidazol-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(64)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.25 mmol), 1-(1H-imidazol-2-yl)methanamine (42 mg,0.25 mmol), DIPEA (164 μl, 0.99 mmol) and HATU (188 mg, 0.50 mmol) inDMF (2 ml) afforded the title compound (65 mg, 54%) as a yellow oilafter purification by flash column chromatography (kp-NH, eluting with agradient 0-5% MeOH/DCM).

HPLCMS (Method A): [m/z]: 482.25 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(morpholin-4-yl)pyridin-4-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(65)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.25 mmol),[3-(morpholin-4-yl)pyridin-4-yl]methanamine (48 mg, 0.25 mmol), DIPEA(164 μl, 0.99 mmol) and HATU (189 mg, 0.50 mmol) in DMF (2 ml) affordedthe title compound (112 mg, 78%) as a yellow solid after purification byflash column chromatography (kp-NH, eluting with a gradient of 50-100%EtOAc/heptane).

HPLCMS (Method A): [m/z]: 578.10 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(66)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.20 mmol, 80% purity),1-(5-methylpyridin-2-yl)methanamine (29 mg, 0.24 mmol), DIPEA (104 μl,0.60 mmol) and HATU (15 1 mg, 0.40 mmol) in DMF (2 ml) afforded thetitle compound (48 mg, 47%) as a colourless oil after purification byflash column chromatography (kp-NH, eluting with a gradient of 0-100%EtOAc/heptane).

HPLCMS (Method A): [m/z]: 507.1 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[6-(dimethylamino)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(67)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.20 mmol, 80% purity),5-(aminomethyl)-N,N-dimethylpyridin-2-amine (30 mg, 0.20 mmol), DIPEA(104 μl, 0.60 mmol) and HATU (151 mg, 0.40 mmol) in DMF (2 ml) affordedthe title compound (36 mg, 34%) as a colourless oil after purificationby flash column chromatography (kp-NH, eluting with a gradient of 0-100%EtOAc/heptane).

HPLCMS (Method A): [m/z]: 536.35 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-methylpyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(68)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.20 mmol, 80% purity),1-(2-methylpyridin-4-yl)methanamine (36 mg, 0.30 mmol), DIPEA (104 μl,0.60 mmol) and HATU (151 mg, 0.40 mmol) in DMF (2 ml) afforded the titlecompound (36 mg, 36%) as a colourless oil after purification by flashcolumn chromatography (kp-NH, eluting with a gradient of 0-100%EtOAc/heptane).

HPLCMS (Method A): [m/z]: 507.3 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(69)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.20 mmol, 80% purity),1-(1,5-dimethyl-1H-pyrazol-4-yl)methanamine (37 mg, 0.30 mmol), DIPEA(104 μl, 0.60 mmol) and HATU (151 mg, 0.40 mmol) in DMF (2 ml) affordedthe title compound (74 mg, 73%) as a colourless oil after purificationby flash column chromatography (kp-NH, eluting with a gradient of 0-100%EtOAc/heptane).

HPLCMS (Method A): [m/z]: 510.15 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(70)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.236 mmol),1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methanamine hydrochloride(87 mg, 0.354 mmol), DIPEA (0.21 ml, 1.18 mmol), and HATU (135 mg, 0.354mmol) in DMF (3 ml) afforded the title compound (216 mg, 69%, 45%purity) as a yellow oil after flash column chromatography (KP—NH,eluting with a gradient of 20-100% EtOAc/heptane). The title compoundwas used in the next step without further purification.

HPLCMS (Method A): [m/z]: 595.1 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-chloro-5-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(71)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.236 mmol),(3-chloro-5-fluoropyridin-2-yl)methanamine hydrochloride (70 mg, 0.354mmol), DIPEA (0.21 ml, 1.18 mmol), and HATU (135 mg, 0.354 mmol) in DMF(3 ml) afforded the title compound (157 mg, 76%, 62% purity) as a yellowoil after flash column chromatography (KP—NH, eluting with a gradient of20-100% EtOAc/heptane). The title compound was used in the next stepwithout further purification.

HPLCMS (Method A): [m/z]: 545.15 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-fluoropyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(72)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.236 mmol, 95% purity),1-(2-fluoropyridin-3-yl)methanamine (47.01 mg, 0.373 mmol), DIPEA (0.13ml, 0.745 mmol) and HATU (141.7 mg, 0.373 mmol) in DMF (2 ml) affordedthe title compound (0.359 g, quant.) as a brown solid after evaporationof the solvent. The title compound was used in the next step withoutfurther purification.

HPLCMS (Method A): [m/z]: 511.10 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-methoxypyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(73)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.236 mmol, 95% purity),1-(2-methoxypyridin-4-yl)methanamine (49 mg, 0.354 mmol), DIPEA (0.12ml, 0.708 mmol) and HATU (135 mg, 0.354 mmol) in DMF (3 ml) afforded thetitle compound (104 mg, 81%, 96% purity) as a white solid afterpurification by flash column chromatography (eluting with a gradient of30-100% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=10.07 (s, 1H), 8.10 (d, J=5.3 Hz, 1H),7.96 (s, 1H), 7.73-7.66 (m, 2H), 7.41-7.37 (m, 1H), 7.25-7.22 (m, 2H),6.85-6.82 (m, 1H), 6.69 (s, 1H), 4.62 (s, 2H), 4.56 (d, J=6.3 Hz, 2H),3.91 (s, 3H), 3.78 (t, J=6.6 Hz, 2H), 3.24 (t, J=6.2 Hz, 2H), 1.39 (s,9H)

HPLCMS (Method A): [m/z]: 523.3 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4,6-dimethylpyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(74)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.236 mmol, 95% purity),(4,6-dimethylpyridin-3-yl)methanamine dihydrochloride (B1) (93 mg, 0.354mmol, 80% purity), DIPEA (0.206 ml, 1.18 mmol) and HATU (135 mg, 0.354mmol) in DMF (3 ml) afforded the title compound (77 mg, 63%) as a yellowoil after purification by flash column chromatography (eluting with agradient of 0-15% MeOH/EtOAc).

HPLCMS (Method A): [m/z]: 521.05 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylpyridin-2-yl)methyl]carbamoyl}1,3-thiazol-2-yl)ethyl]carbamate(75)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.236 mmol, 95% purity),(4,6-dimethylpyridin-3-yl)methanamine dihydrochloride (93 mg, 0.354mmol), DIPEA (0.123 ml, 0.708 mmol) and HATU (135 mg, 0.354 mmol) in DMF(2 ml) afforded the title compound (90 mg, 72%) as a yellow oil afterpurification by flash column chromatography (KP—NH, eluting with agradient of 20-100% EtOAc/heptane followed by 0-20% MeOH/EtOAc).

HPLCMS (Method A): [m/z]: 507.10 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-(5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)-1,3-thiazol-2-yl]ethyl}carbamate(76)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.236 mmol, 95% purity),5,6,7,8-tetrahydro-1,6-naphthyridine dihydrochloride (62 mg, 0.298mmol), DIPEA (0.173 ml, 0.994 mmol) and HATU (151 mg, 0.398 mmol) in DMF(2 ml) afforded the title compound (90 mg, 72%) as a colourless oilafter purification by flash column chromatography (kp-NH, eluting with agradient of 0-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 519.15 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(77)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (100 mg, 0.236 mmol, 95% purity),(3,5-difluoropyridin-2-yl)methanamine dihydrochloride (65 mg, 0.298mmol), DIPEA (0.173 ml, 0.994 mmol) and HATU (151 mg, 0.398 mmol) in DMF(3 ml) afforded the title compound (112 mg, quant.) as a colourless oilafter purification by flash column chromatography (kp-NH, eluting with agradient of 0-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 529.10 [M+H]⁺

Tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (78)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (15.94 mg, 0.04 mmol),(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methanamine (C3)(10 mg, 0.04 mmol), DIPEA (0.03 ml, 0.16 mmol) and HATU (30.13 mg, 0.08mmol) in DMF (2 ml) afforded the title compound (17.5 mg, 34%, 30%purity) as an orange oil after purification by flash columnchromatography (eluting with a gradient of 0-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 637.15 [M+H]⁺

Tert-butyl2-{[(2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazol-4-yl)formamido]methyl}piperidine-1-carboxylate(79)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (200 mg, 0.5 mmol), tert-butyl2-(aminomethyl)piperidine-1-carboxylate (149 mg, 0.7 mmol), TEA (66.16μl, 0.5 mmol) and HATU (280 mg, 0.75 mmol) in DMF (5 ml) at roomtemperature for 2 h, afforded the title compound (50 mg, 17%) as anorange oil after purification by flash column chromatography (elutingwith a gradient of 0-100% EtOAc/heptane) followed by basic prep-HPLC.

HPLCMS (Method A): [m/z]: 599.4 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 12)

In a similar fashion to general procedure 2, 4M HCl in dioxane (11 ml)and tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(9) (2.2 g, 4.47 mmol) in dioxane (30 ml) at room temperature for 16 h,gave the title compound (HCl salt) (1.7 g, 76%) as a yellow solid aftertrituration from Et₂O (2×30 ml) followed by DCM (2×20 ml) and Et₂O (2×30ml).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=10.39 (s, 1H), 9.68 (t, J=6.0 Hz, 1H),8.86-8.75 (m, 1H), 8.44 (td, J=7.9, 1.5 Hz, 1H), 8.30 (s, 1H), 7.96-7.84(m, 2H), 7.76 (dt, J=6.5, 3.3 Hz, 2H), 7.44 (dq, J=6.5, 3.4 Hz, 2H),4.86 (d, J=6.0 Hz, 2H), 4.76 (s, 2H), 3.66 (dt, J=38.8, 7.1 Hz, 4H)

HPLCMS (Method C): [m/z]: 493.4 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(thiophen-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 16)

In a similar fashion to general procedure 7, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(thiophen-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(12) (180 mg, 0.362 mmol) and 50% TFA in DCM (10 ml) at room temperatureovernight gave the title compound (51 mg, 34%, 98% purity) as a whiteoil after purification by prep-HPLC.

1H-NMR (CDCl₃, 400 MHz): d[ppm]=8.05 (s, 1H), 7.59 (m, 3H), 7.24 (m,2H), 7.21-7.19 (dd, J=5.1, 1.2 Hz, 1H), 7.01 (m, 1H), 6.94 (m, 1H), 4.78(d, J=6.0, 2H), 4.15 (s, 2H), 3.27-3.07 (m, 4H)

HPLCMS (Method J): [m/z]: 398.5 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-methyl-N-phenyl-1,3-thiazole-4-carboxamide(Example Compound No. 19)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[methyl(phenyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(15) (110.12 mg, 0.224 mmol) and 50% TFA in DCM (10 ml) at roomtemperature overnight gave the title compound (40 mg, 45%, 85% purity)as a white oil after purification by flash column chromatography(eluting with a gradient of 0-10% MeOH in DCM).

1H-NMR (CDCl₃, 400 MHz): d[ppm]=7.69 (bs, 2H), 7.29-7.21 (m, 5H), 7.10(s, 2H), 4.28 (s, 2H), 3.60-3.43 (m, 3H), 3.18 (bs, 2H), 3.05 (bs, 2H)

HPLCMS (Method J): [m/z]: 392.5 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(pyrrolidin-1-yl)phenyl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 21)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(pyrrolidin-1-yl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(16) (100 mg, 0.178 mmol) and 50% TFA in DCM (8 ml) at room temperatureovernight gave the title compound (70 mg, 69%, 82% purity) as a whiteoil after purification by flash column chromatography (eluting with agradient of 5-7% MeOH in DCM).

1H-NMR (CDCl₃, 400 MHz): d[ppm]=7.94 (s, 1H), 7.85 (t, J=5.6 Hz, 1H),7.53-7.47 (m, 2H), 7.24-7.16 (m, 2H), 7.12 (t, J=7.8 Hz, 1H), 6.59 (d,J=7.5 Hz, 1H), 6.48 (s, 1H), 6.43 (d, J=8.1 Hz, 1H), 4.53 (d, J=5.9 Hz,2H), 4.14 (s, 2H), 3.21 (m, 4H), 3.12-3.05 (m, 4H), 2.00-1.90 (m, 4H)

HPLCMS (Method J): [m/z]: 461.6 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-3-ylmethyl)-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 35)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(22) (184 mg, 0.374 mmol) and 4M HCl in dioxane (15 ml) at roomtemperature for 18 h gave the title compound (80 mg, 53%) as the tri HClsalt as a white solid after precipitation with Et₂O.

1H-NMR (DMSO-d6, 400 MHz): d[ppm]=10.28 (bs, 3H), 9.64 (t, J=6.2 Hz,1H), 8.90 (s, 1H), 8.81 (d, J=5.4 Hz, 1H), 8.55 (d, J=8.1 Hz, 1H), 8.25(s, 1H), 8.00 (dd, J=8.0, 5.7 Hz, 1H), 7.73 (m, 2H), 7.48-7.34 (m, 2H),4.71 (s, 2H), 4.65 (d, J=6.2 Hz, 2H), 3.66 (t, J=6.6 Hz, 2H), 3.57 (t,J=6.3 Hz, 2H)

HPLCMS (Method J): [m/z]: 493.3 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-4-ylmethyl)-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 36)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridin-4-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(23) (145.8 mg, 0.296 mmol) and 4M HCl in dioxane (15 ml) at roomtemperature for 18 h gave the title compound (70 mg, 47%) as the tri HClsalt as a white solid after precipitation with Et₂O.

1H-NMR (DMSO, 400 MHz): d[ppm]=10.40 (bs, 3H), 9.69 (t, J=6.2 Hz, 1H),8.83 (d, J=6.7 Hz, 2H), 8.28 (s, 1H), 7.98 (d, J=6.6 Hz, 2H), 7.81-7.69(m, 2H), 7.49-7.37 (m, 2H), 4.73 (d, J=5.1 Hz, 4H), 3.68 (t, J=6.5 Hz,2H), 3.60 (t, J=6.4 Hz, 2H)

HPLCMS (Method J): [m/z]: 493.3 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 37)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(24) (86.33 mg, 0.154 mmol) and 4M HCl in dioxane (10 ml) at roomtemperature for 18 h gave the title compound (25 mg, 35%) as a yellowoil after purification by flash column chromatography (eluting with agradient of 10-15% MeOH in DCM).

1H-NMR (MeOD, 400 MHz): d[ppm]=8.62 (d, J=4.8 Hz, 1H), 8.13-8.09 (m,1H), 8.08 (s, 1H), 7.52-7.47 (m, 2H), 7.47-7.41 (m, 1H), 7.22-7.14 (m,2H), 4.86 (s, 2H), 4.09 (s, 2H), 3.27 (t, J=6.6 Hz, 2H), 3.13 (t, J=6.6Hz, 2H)

HPLCMS (Method J): [m/z]: 461.6 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(5,6,7,8-tetrahydroquinolin-8-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 38)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(5,6,7,8-tetrahydroquinolin-8-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(25) (82.03 mg, 0.154 mmol) and 4M HCl in dioxane (10 ml) at roomtemperature for 18 h gave the title compound (35 mg, 52%) as a yellowoil after purification by flash column chromatography (eluting with agradient of 10-15% MeOH in DCM).

1H-NMR (MeOD, 400 MHz): d[ppm]=8.27 (d, J=3.6 Hz, 1H), 8.08 (s, 1H),7.58 (d, J=7.6 Hz, 1H), 7.49 (m, 2H), 7.27-7.15 (m, 3H), 5.22-5.12 (m,1H), 4.05 (s, 2H), 3.21 (t, J=6.7 Hz, 2H), 3.05 (t, J=6.4 Hz, 2H),2.96-2.77 (m, 2H), 2.34-2.20 (m, 1H), 2.05-1.79 (m, 3H)

HPLCMS (Method J): [m/z]: 433.6 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 39)

In a similar fashion to general procedure 2, 4M HCl in dioxane (6.36 ml)was added to tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol2-yl]ethyl}carbamate (26) (1.32 g, 2.55 mmol) in dioxane (30 ml) andstirred at room temperature for 48 h to give the title compound (1.03 g,76%) after crystalisation from DCM/MeOH.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.56 (d, J=5.8 Hz, 1H), 8.52-8.48 (m,1H), 8.31 (s, 1H), 7.92 (dd, J=7.7, 6.0 Hz, 1H), 7.86 (dt, J=6.7, 3.3Hz, 2H), 7.66 (dt, J=6.3, 3.3 Hz, 2H), 5.95 (t, J=8.8 Hz, 1H), 5.01 (s,2H), 3.87 (t, J=6.2 Hz, 2H), 3.71-3.63 (m, 2H), 3.42-3.35 (m, 1H), 3.21(dt, J=17.1, 8.7 Hz, 1H), 2.86-2.77 (m, 1H), 2.51 (dq, J=12.9, 9.2 Hz,1H)

HPLCMS (Method C): [m/z]: 419.05 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide trihydrochloride (ExampleCompound No. 40)

In a similar fashion to general procedure 2, 4M HCl in dioxane (16.57ml, 66.26 mmol) was added to tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(27) (4.13 g, 6.63 mmol) in dioxane (40 ml) and stirred at roomtemperature for 16 h to give the title compound (3.04 g, 88%) as a whitesolid after precipitation from Et₂O (100 ml).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.47 (d, J=5.1 Hz, 1H), 8.28 (s, 1H),8.11 (s, 1H), 7.84 (dd, J=6.1, 3.1 Hz, 2H), 7.76 (s, 1H), 7.62 (dd,J=6.1, 3.0 Hz, 2H), 4.99 (s, 2H), 4.95 (s, 2H), 3.84 (t, J=6.2 Hz, 2H),3.65 (t, J=6.2 Hz, 2H)

HPLCMS (Method D): [m/z]: 411.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-methylpyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 42)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(29) (79.5 mg, 0.157 mmol) and 4M HCl in dioxane (15 ml) at roomtemperature overnight gave the title compound (25.5 mg, 36%) as a paleyellow oil after purification by flash column chromatography (elutingwith a gradient of 10-15% MeOH in DCM).

1H-NMR (MeOD, 400 MHz): d[ppm]=8.09 (s, 1H), 7.63 (t, J=7.7 Hz, 1H),7.50 (m, 2H), 7.23-7.17 (m, 3H), 7.15 (m, 2H), 4.63 (s, 2H), 4.08 (s,2H), 3.26 (t, J=6.7 Hz, 2H), 3.11 (t, J=6.6 Hz, 2H), 2.50 (s, 3H)

HPLCMS (Method J): [m/z]: 405.5 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(5-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound No. 43)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(30) (80.2 mg, 0.157 mmol) and 4M HCl in dioxane (15 ml) at roomtemperature overnight gave the title compound (12.5 mg, 17%) as a paleyellow oil after purification by flash column chromatography (elutingwith a gradient of 10-15% MeOH in DCM).

1H-NMR (MeOD, 400 MHz): d[ppm]=8.36 (d, J=2.6 Hz, 1H), 8.08 (s, 1H),7.59-7.46 (m, 3H), 7.42 (m, 1H), 7.20 (m, 2H), 4.66 (s, 2H), 4.08 (s,2H), 3.26 (t, J=6.5 Hz, 2H), 3.11 (t, J=6.5 Hz, 2H)

HPLCMS (Method J): [m/z]: 411.5 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyrimidin-4-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 44)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrimidin-4-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(31) (75 mg, 0.152 mmol) and 4M HCl in dioxane (2 ml) at roomtemperature for 4 h gave the title compound (22 mg, 37%) as a yellowsolid after purification by flash column chromatography (eluting with agradient of 8% MeOH in DCM).

1H-NMR (MeOD, 400 MHz): d[ppm]=9.05 (d, J=1.1 Hz, 1H), 8.67 (d, J=5.3Hz, 1H), 8.12 (s, 1H), 7.51 (dd, J=6.0, 3.2 Hz, 2H), 7.46 (d, J=5.3 Hz,1H), 7.26-7.18 (m, 2H), 4.68 (s, 2H), 4.10 (s, 2H), 3.28 (t, J=6.5 Hz,2H), 3.14 (t, J=6.6 Hz, 2H)

HPLCMS (Method J): [m/z]: 394.4 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(5-methoxypyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 45)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methoxypyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(32) (80 mg, 0.153 mmol) and 4M HCl in dioxane (2 ml) at roomtemperature for 4 h gave the title compound (53 mg, 82%) as a yellowsolid after purification by flash column chromatography (eluting with agradient of 8% MeOH in DCM).

1H-NMR (MeOD, 400 MHz): d[ppm]=8.17-8.13 (m, 1H), 8.08 (s, 1H),7.54-7.47 (m, 2H), 7.35-7.31 (m, 2H), 7.25-7.18 (m, 2H), 4.61 (s, 2H),4.07 (d, J=8.0 Hz, 2H), 3.84 (s, 3H), 3.26 (t, J=6.6 Hz, 2H), 3.11 (t,J=6.6 Hz, 2H)

HPLCMS (Method J): [m/z]: 423.4 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyrazin-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 46)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyrazin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(33) (70 mg, 0.142 mmol) and 4M HCl in dioxane (2 ml) at roomtemperature for 4 h gave the title compound (30 mg, 53.7%) as a brownsolid after purification by flash column chromatography (eluting with agradient of 8% MeOH in DCM).

1H-NMR (MeOD, 400 MHz): d[ppm]=8.63 (s, 1H), 8.56-8.51 (m, 1H), 8.48 (d,J=2.6 Hz, 1H), 8.12 (s, 1H), 7.52 (dd, J=6.0, 3.2 Hz, 2H), 7.22 (dd,J=6.1, 3.1 Hz, 2H), 4.74 (s, 2H), 4.13 (s, 2H), 3.28 (t, J=6.5 Hz, 2H),3.17 (t, J=6.5 Hz, 2H)

HPLCMS (Method I): [m/z]: 394.4 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-oxo-1,6-dihydropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 47)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-oxo-1,6-dihydropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(34) (70 mg, 0.138 mmol) and 4M HCl in dioxane HCl (2 ml) at roomtemperature for 4 h gave the title compound (30 mg, 53%) as a yellowsolid after purification by flash column chromatography (eluting with agradient of 8% MeOH in DCM).

1H-NMR (MeOD, 400 MHz): d[ppm]=8.12 (s, 1H), 7.51 (m, 3H), 7.22 (dd,J=6.0, 3.2 Hz, 2H), 6.42 (d, J=9.1 Hz, 1H), 6.30 (d, J=6.9 Hz, 1H), 4.44(s, 2H), 4.09 (s, 2H), 3.27 (t, J=6.7 Hz, 2H), 3.12 (t, J=6.7 Hz, 2H)

HPLCMS (Method J): [m/z]: 409.4 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-cyanopyridin-3-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 56) and5-{[(2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazol-4-yl)formamido]methyl}pyridine-2-carboxamide(Example Compound No. 54)

In a similar fashion to general procedure 2, a mixture of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-carbamoylpyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(35) and tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-cyanopyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(36) (80 mg, 0.155 mmol) and 4 M HCl in dioxane (3 ml) at roomtemperature for 18 h gave two products. Formamide (Example Compound No.54) (16 mg, 23%) was isolated following flash column chromatography(eluting with a gradient of DCM/MeOH, 9:1). Crude nitrile (ExampleCompound No. 56) was also isolated and was further purified by basicprep-HPLC to give the required product as a brown solid (24 mg, 37%).

Formamide: 1H-NMR (Methanol-d4, 400 MHz): d[ppm]=8.49 (t, J=10.2 Hz,1H), 7.99 (s, 1H), 7.94 (t, J=10.0 Hz, 1H), 7.78 (dt, J=8.1, 4.0 Hz,1H), 7.46-7.34 (m, 2H), 7.11 (dd, J=6.0, 3.1 Hz, 2H), 4.56 (d, J=14.2Hz, 2H), 4.02 (d, J=8.0 Hz, 2H), 3.19 (m, 4H), 3.06 (t, J=6.5 Hz, 2H)

HPLCMS (Method I): [m/z]: 436.5 [M+H]⁺

Nitrile: 1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 9.08 (t, J=6.2Hz, 1H), 8.70 (s, 1H), 8.14 (s, 1H), 7.97 (d, J=8.0 Hz, 1H), 7.92 (dd,J=8.1, 2.0 Hz, 1H), 7.48 (d, J=29.4 Hz, 2H), 7.12 (d, J=4.7 Hz, 2H),4.54 (d, J=6.2 Hz, 2H), 4.10 (d, J=5.2 Hz, 1H), 3.96 (s, 2H), 3.18-3.15(m, 2H), 2.98 (d, J=6.6 Hz, 2H)

HPLCMS (Method I): [m/z]: 418.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3,5-dimethylpyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 57)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3,5-dimethylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(37) (198 mg, 0.36 mmol) and 12 M HCl (0.307 ml, 8.42 mmol) in MeOH (10ml) at 40° C. for 21 h gave the title compound (90 mg, 59%) as a yellowsolid after purification by neutral prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.71 (t, J=4.8 Hz, 1H),8.16 (s, 1H), 8.14 (s, 1H), 7.51 (s, 1H), 7.42 (s, 2H), 7.12 (d, J=4.9Hz, 2H), 4.52 (d, J=4.9 Hz, 2H), 3.97 (s, 2H), 3.17 (d, J=4.9 Hz, 2H),2.98 (t, J=6.8 Hz, 2H), 2.27 (s, 3H), 2.24 (s, 3H)

HPLCMS (Method B): [m/z]: 421.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 61)

In a similar fashion to general procedure 2, tert-butyl2-({[(tert-butoxy)carbonyl](2-{4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)amino}methyl)-1H-1,3-benzodiazole-1-carboxylate(38) (86 mg, 0.145 mmol) and 12 M HCl (0.282 ml, 3.378 mmol) in MeOH (2ml) at 40° C. for 24 h gave the title compound (24 mg, 42%) as a brownsolid after purification by flash column chromatography (eluting with agradient 100% DCM, 90% DCM: 10% MeOH and 90% DCM:10% methanolic ammonia)followed by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 8.75 (dd, J=10.2, 5.4Hz, 3H), 8.13 (s, 1H), 7.48 (d, J=36.0 Hz, 2H), 7.39 (t, J=4.9 Hz, 1H),7.19-7.03 (m, 2H), 4.66 (d, J=5.8 Hz, 2H), 3.97 (s, 2H), 3.20 (t, J=6.8Hz, 2H), 2.99 (t, J=6.8 Hz, 2H), 2.66 (s, 1H)

HPLCMS (Method B): [m/z]: 394.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(4-methylpiperazin-1-yl)phenyl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 68)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(4-methylpiperazin-1-yl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(39) (13.4 mg, 0.02 mmol) in dioxane (0.5 ml) and 4M HCl in dioxane(55.1 μl) at 50° C. for 16 h gave the title compound (11.5 mg, 85%) as awhite solid after trituration with DCM.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.28 (s, 1H), 7.88 (dt, J=6.6, 3.3Hz, 2H), 7.69 (dt, J=6.3, 3.3 Hz, 2H), 7.45 (t, J=7.6 Hz, 1H), 7.33 (d,J=6.7 Hz, 2H), 7.20-7.14 (m, 1H), 5.06 (s, 2H), 4.78 (s, 2H), 3.87 (t,J=6.2 Hz, 2H), 3.72-3.59 (m, 4H), 3.49 (t, J=10.5 Hz, 2H), 3.37 (s, 2H),3.27 (d, J=11.0 Hz, 2H), 3.02 (s, 3H)

HPLCMS (Method D): [m/z]: 490.3 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2,6-difluorophenyl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 69)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2,6-difluorophenyl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(40) (90 mg, 0.17 mmol) in dioxane (2 ml) and 4M HCl in dioxane (427 μl)at room temperature for 16 h gave the title compound (15 mg, 20.6%) as aoff white solid after purification by prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.06 (s, 1H), 7.53 (dd, J=5.8, 3.2Hz, 2H), 7.34 (tt, J=8.4, 6.5 Hz, 1H), 7.29-7.16 (m, 2H), 7.03-6.88 (m,2H), 4.68 (s, 2H), 4.07 (s, 2H), 3.23 (t, J=6.6 Hz, 2H), 3.09 (t, J=6.6Hz, 2H)

HPLCMS (Method A): [m/z]: 428.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(dimethylamino)phenyl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 70)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(dimethylamino)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(41) (73 mg, 0.14 mmol) in dioxane (2 ml) and 4M HCl in dioxane (341 μl)at 50° C. for 16 h gave title compound (8.7 mg, 14%) followingpurification by prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.08 (s, 1H), 7.53 (dd, J=5.9, 3.2Hz, 2H), 7.29-7.14 (m, 5H), 7.02 (td, J=7.4, 1.1 Hz, 1H), 4.68 (s, 2H),4.08 (s, 2H), 3.25 (t, J=6.7 Hz, 2H), 3.11 (t, J=6.8 Hz, 2H), 2.67 (s,6H)

HPLCMS (Method D): [m/z]: 435.3 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-cyanophenyl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 71)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-cyanophenyl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(42) (54 mg, 0.1 mmol) in dioxane (2 ml) and 4M HCl in dioxane (261 μl)at 50° C. for 12 h gave the title compound (8 mg, 18%) as a yellow solidafter purification by prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.11 (s, 1H), 7.74-7.69 (m, 1H),7.60 (td, J=7.8, 1.2 Hz, 1H), 7.56-7.50 (m, 3H), 7.43 (t, J=7.6 Hz, 1H),7.25-7.19 (m, 2H), 4.78 (s, 2H), 4.09 (s, 2H), 3.27 (t, J=6.6 Hz, 2H),3.13 (t, J=6.6 Hz, 2H)

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(trifluoromethoxy)phenyl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 72)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(trifluoromethoxy)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(43) (110 mg, 0.191 mmol), 12M HCl (0.317 ml, 4.458 mmol) in MeOH (2 ml)at room temperature for 16 h, gave the title compound (41 mg, 45%) as awhite solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.19 (s, 1H), 8.88 (t, J=6.2 Hz, 1H),8.15 (s, 1H), 7.48 (d, J=31.2 Hz, 2H), 7.42-7.30 (m, 4H), 7.13 (d, J=4.9Hz, 2H), 4.53 (d, J=6.3 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J=6.8 Hz, 2H),2.99 (t, J=6.8 Hz, 2H)

HPLCMS (Method A): [m/z]: 476.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(difluoromethoxy)phenyl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 74)

In a similar fashion to general procedure 2, crude tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(difluoromethoxy)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(45) (470 mg), 12 M HCl (5 ml) in MeOH (5 ml) at 50° C. for 2 h,afforded the title compound (56 mg, 35%) as a pale yellow solid afterpurification by flash column chromatography (KP—NH, eluting with agradient of 0-15% MeOH/DCM) followed by prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 8.79 (t, J=6.2 Hz, 1H),8.13 (s, 1H), 7.47 (s, 2H), 7.35-7.28 (m, 2H), 7.25-7.06 (m, 5H), 4.48(d, J=6.2 Hz, 2H), 3.96 (s, 2H), 3.22-3.17 (m, 2H), 2.98 (t, J=6.8 Hz,2H)

HPLCMS (Method D): [m/z]: 458.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(morpholine-4-sulfonyl)phenyl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 75)

In a similar fashion to general procedure 2, crude tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(morpholine-4-sulfonyl)phenyl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(46) (440 mg), 12M HCl (5 ml) in MeOH (5 ml) at 50° C. for 2 h, affordedthe title compound (67 mg, 42%) as a pale yellow solid afterpurification by flash column chromatography (KP—NH, eluting with agradient of 0-15% MeOH/DCM) followed by prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.19 (s, 1H), 8.88 (t, J=6.3 Hz, 1H),8.17 (s, 1H), 7.84 (d, J=7.9 Hz, 1H), 7.66 (t, J=7.6 Hz, 1H), 7.50 (dd,J=11.8, 7.7 Hz, 4H), 7.17-7.06 (m, 2H), 4.81 (d, J=6.2 Hz, 2H), 3.97 (s,2H), 3.70-3.61 (m, 4H), 3.20 (t, J=6.8 Hz, 2H), 3.10-3.04 (m, 4H), 2.99(t, J=6.7 Hz, 2H)

HPLCMS (Method D): [m/z]: 541.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[2-(pyridin-2-yl)ethyl]-1,3-thiazole-4-carboxamide(Example Compound No. 76)

In a similar fashion to general procedure 2, dioxane (2 ml) was added totert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[2-(pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(47) (52 mg, 0.103 mmol) and 4 M HCl in dioxane (257 μl, 1.03 mmol). Thereaction mixture was stirred at room temperature for 16 h to afford thetitle compound (11 mg, 26%) as a tan solid after purification by neutralprep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.44 (ddd, J=5.0, 1.7, 0.8 Hz,1H), 8.03 (s, 1H), 7.72 (td, J=7.7, 1.8 Hz, 1H), 7.55 (dd, J=5.8, 3.2Hz, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.29-7.19 (m, 3H), 4.09 (s, 2H), 3.74(t, J=7.1 Hz, 2H), 3.25 (t, J=6.7 Hz, 2H), 3.13-3.05 (m, 4H)

HPLCMS (Method B): [m/z]: 407.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(3-fluoropyridin-2-yl)-1,3-thiazole-4-carboxamide(Example Compound No. 77)

In a similar fashion to general procedure 2, dioxane (4 ml) was added tocrude tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(3-fluoropyridin-2-yl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(48) (705 mg) and 4M HCl in dioxane (1.56 ml, 6.24 mmol). The reactionmixture was stirred at room temperature for 16 h to afford the titlecompound (10 mg, 3.9%) as a tan solid after purification by neutralprep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.37 (s, 1H), 8.29 (dd, J=4.7, 1.0Hz, 1H), 7.75 (ddd, J=9.8, 8.4, 1.4 Hz, 1H), 7.52 (dd, J=6.1, 3.2 Hz,2H), 7.41 (ddd, J=8.4, 4.7, 3.8 Hz, 1H), 7.24 (dd, J=6.1, 3.2 Hz, 2H),4.44 (s, 2H), 3.56-3.46 (m, 4H)

HPLCMS (Method D): [m/z]: 397.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoro-6-methylpyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 79)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.36 ml)was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoro-6-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(50) (76 mg, 0.14 mmol) in dioxane (2 ml) and the mixture was stirred atroom temperature for 16 h, to give the title compound (24 mg, 39%) as acolourless oil after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.09 (s, 1H), 7.55-7.42 (m, 3H),7.29-7.14 (m, 3H), 4.71 (d, J=1.7 Hz, 2H), 4.09 (s, 2H), 3.27 (t, J=6.7Hz, 2H), 3.14 (t, J=6.7 Hz, 2H), 2.45 (s, 3H)

HPLCMS (Method D): [m/z]: 425.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[1-(pyridin-2-yl)ethyl]-1,3-thiazole-4-carboxamide(Example Compound No. 80)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.39 ml,1.56 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[1-(pyridin-2-yl)ethyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(51) (78 mg, 0.15 mmol) in dioxane (2 ml) and the mixture was stirred atroom temperature for 16 h, to give the title compound (15 mg, 23%) as acolourless oil after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.48 (ddd, J=4.9, 1.7, 0.9 Hz,1H), 8.08 (s, 1H), 7.79 (td, J=7.8, 1.7 Hz, 1H), 7.54 (dd, J=5.7, 3.2Hz, 2H), 7.45 (d, J=7.8 Hz, 1H), 7.29 (ddd, J=7.5, 4.9, 1.1 Hz, 1H),7.26-7.18 (m, 2H), 5.25 (d, J=7.0 Hz, 1H), 4.11 (s, 2H), 3.29 (t, J=6.7Hz, 2H), 3.16-3.12 (m, 2H), 1.57 (d, J=7.0 Hz, 3H)

HPLCMS (Method D): [m/z]: 407.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 81)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.41 ml,1.64 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[6-(trifluoromethyl)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(52) (92 mg, 0.16 mmol) in dioxane (2 ml) and the mixture was stirred atroom temperature for 16 h, to afford the title compound (21 mg, 27%) asa colourless oil after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.71 (d, J=1.5 Hz, 1H), 8.11 (s,1H), 8.00 (dd, J=8.1, 1.5 Hz, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.53 (dd,J=5.8, 3.2 Hz, 2H), 7.28-7.14 (m, 2H), 4.68 (s, 2H), 4.09 (s, 2H), 3.27(t, J=6.7 Hz, 2H), 3.12 (t, J=6.7 Hz, 2H)

HPLCMS (Method D): [m/z]: 461.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 82)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(53) (161 mg, 0.363 mmol) and 12M HCl (1.6 ml, 19.2 mmol) in MeOH (1.6ml) at 50° C. for 4 h, afforded the title compound (72 mg, 54%) as awhite solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.22 (s, 1H), 8.71 (t, J=5.5 Hz, 1H),8.47 (dd, J=4.7, 1.3 Hz, 1H), 8.15 (s, 1H), 7.95 (dd, J=8.1, 1.3 Hz,1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.37 (dd, J=8.1, 4.7 Hz, 1H), 7.12 (d,J=4.8 Hz, 2H), 4.67 (d, J=5.5 Hz, 2H), 3.97 (s, 2H), 3.20 (t, J=6.8 Hz,2H), 2.98 (t, J=6.8 Hz, 2H)

HPLCMS (Method D): [m/z]: 427.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-oxo-1,2-dihydropyridin-3-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 83)

In a similar fashion to general procedure 2, crude tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(tert-butoxy)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(54) (205 mg, 0.36 mmol) and 12M HCl (2 ml) in MeOH (2 ml) at 50° C. for4 h, afforded the title compound (66 mg, 44%) as a pale yellow solidafter purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (br s, 1H), 11.65 (br s, 1H),8.59 (t, J=6.0 Hz, 1H), 8.11 (s, 1H), 7.48 (s, 2H), 7.32-7.26 (m, 1H),7.24 (d, J=6.7 Hz, 1H), 7.12 (dd, J=6.0, 3.1 Hz, 2H), 6.15 (t, J=6.6 Hz,1H), 4.22 (d, J=6.0 Hz, 2H), 3.96 (s, 2H), 3.21-3.14 (m, 2H), 2.97 (t,J=6.8 Hz, 2H)

HPLCMS (Method D): [m/z]: 409.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-imidazol-5-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 84)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-imidazol-5-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(55) (148 mg, 0.3 mmol) and 4M HCl in dioxane (7 ml) at room temperaturefor 2 h, afforded title compound (58 mg, 49%) as a colourless glassafter purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.66 (t, J=6.0 Hz, 1H), 8.13 (s, 1H),7.60-7.31 (m, 3H), 7.28-6.97 (m, 2H), 6.79 (s, 1H), 4.41 (d, J=6.0 Hz,2H), 3.96 (s, 2H), 3.60 (s, 3H), 3.16 (t, J=6.8 Hz, 2H), 2.97 (t, J=6.8Hz, 2H)

HPLCMS (Method B): [m/z]: 396.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(1,3-oxazol-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 85)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.49 ml,1.96 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1,3-oxazol-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(56) (95 mg, 0.196 mmol) in dioxane (2 ml) and the mixture was stirredat room temperature for 3 h, to give the title compound (13 mg, 17%) asa pale yellow oil after purification by neutral prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.11 (s, 1H), 7.87 (d, J=0.8 Hz,1H), 7.54 (dd, J=5.9, 3.2 Hz, 2H), 7.27-7.18 (m, 2H), 7.13 (d, J=0.8 Hz,1H), 4.70 (s, 2H), 4.10 (s, 2H), 3.27 (t, J=6.6 Hz, 2H), 3.13 (t, J=6.6Hz, 2H)

HPLCMS (Method D): [m/z]: 383.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-pyrazol-3-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 86)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.27 ml,1.08 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(57) (53 mg, 0.11 mmol) in dioxane (2 ml) at room temperature for 3 h,to give the title compound (16 mg, 38%) as a transparent oil afterpurification by neutral prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.08 (s, 1H), 7.57-7.46 (m, 3H),7.28-7.15 (m, 2H), 6.22 (d, J=2.2 Hz, 1H), 4.55 (s, 2H), 4.08 (s, 2H),3.84 (s, 3H), 3.25 (t, J=6.7 Hz, 2H), 3.10 (t, J=6.7 Hz, 2H)

HPLCMS (Method D): [m/z]: 396.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 87)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.51 ml,2.04 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(58) (101 mg, 0.2 mmol) in dioxane (2 ml) at 50° C. for 1 h, to give thetitle compound (15 mg, 19%) as a tan solid after purification by neutralprep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=9.10 (dd, J=4.8, 1.7 Hz, 1H), 8.12(s, 1H), 7.76-7.64 (m, 2H), 7.53 (dd, J=6.0, 3.2 Hz, 2H), 7.22 (dd,J=6.0, 3.2 Hz, 2H), 4.89 (s, 2H), 4.10 (s, 2H), 3.28 (t, J=6.6 Hz, 2H),3.13 (t, J=6.6 Hz, 2H)

HPLCMS (Method D): [m/z]: 394.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-pyrazol-5-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 88)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.26 ml,1.04 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-5-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(59) (51 mg, 0.103 mmol) in dioxane (2 ml) at 50° C. for 1 h, to givethe title compound (12 mg, 30%) as an orange oil after purification byneutral prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.10 (s, 1H), 7.53 (dd, J=6.0, 3.2Hz, 2H), 7.36 (d, J=1.9 Hz, 1H), 7.23 (dd, J=6.0, 3.2 Hz, 2H), 6.25 (d,J=1.9 Hz, 1H), 4.63 (s, 2H), 4.08 (s, 2H), 3.89 (s, 3H), 3.26 (t, J=6.7Hz, 2H), 3.11 (t, J=6.7 Hz, 2H)

HPLCMS (Method D): [m/z]: 396.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-4-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound No. 89)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-fluoropyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(60) (137 mg, 0.191 mmol, 71% purity) and 12M HCl (1.4 ml, 16.8 mmol) inMeOH (1.4 ml) at 50° C. for 2 h afforded the title compound (46 mg, 59%)as a pale yellow solid after purification by neutral prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 8.99 (t, J=6.1 Hz, 1H),8.49 (d, J=1.6 Hz, 1H), 8.35 (d, J=4.8 Hz, 1H), 8.15 (s, 1H), 7.48 (brs, 2H), 7.35-7.26 (m, 1H), 7.12 (d, J=3.5 Hz, 2H), 4.52 (d, J=6.1 Hz,2H), 3.97 (s, 2H), 3.19 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H)

HPLCMS (Method B): [m/z]: 411.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-methylpyridin-4-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 90)

In a similar fashion to general procedure 2, 4M HCl in dioxane (1.8 ml)was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-methylpyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(61) (363 mg, 0.72 mmol) in dioxane (5 ml) at room temperature for 16 hto afford the title compound (203 mg, 55%) as a white solid. The solidwas obtained from precipitation from DCM/MeOH on addition of heptane,followed by a wash with Et₂O.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.69 (s, 1H), 8.60 (d, J=6.1 Hz,1H), 8.30 (s, 1H), 8.00 (d, J=6.1 Hz, 1H), 7.83 (dt, J=6.5, 3.3 Hz, 2H),7.61 (dt, J=6.5, 3.3 Hz, 2H), 5.00 (s, 2H), 3.89 (t, J=6.3 Hz, 2H), 3.69(t, J=6.3 Hz, 2H), 2.63 (s, 3H) (a CH₂ signal obscured by solvent)

HPLCMS (Method B): [m/z]: 407.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-pyrazol-4-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 91)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1-methyl-1H-pyrazol-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(62) (125 mg, 0.25 mmol) and 12M HCl (0.49 ml, 5.88 mmol) in MeOH (5 ml)at 50° C. for 2 h, gave the title compound (42 mg, 42%) as ayellow/brown solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.55 (t, J=6.0 Hz, 1H),8.08 (s, 1H), 7.55 (s, 1H), 7.48 (d, J=38.4 Hz, 2H), 7.32 (s, 1H),7.20-7.03 (m, 2H), 4.25 (d, J=6.0 Hz, 2H), 3.95 (s, 2H), 3.76 (s, 3H),3.15 (t, J=6.8 Hz, 2H), 2.95 (t, J=6.8 Hz, 2H)

HPLCMS (Method D): [m/z]: 396.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(6-methylpyridazin-3-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 93)

In a similar fashion to general procedure 2, crude tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(6-methylpyridazin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(63) (99 mg, 0.154 mmol, 79% purity) and 12M HCl (1 ml) in MeOH (1 ml)at 50° C. for 2 h gave the title compound (32 mg, 51%) as a light-brownsolid after purification by neutral prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 9.01 (t, J=6.1 Hz, 1H),8.14 (s, 1H), 7.57-7.39 (m, 4H), 7.13 (s, 2H), 4.70 (d, J=6.1 Hz, 2H),3.96 (s, 2H), 3.19 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H), 2.58 (s,3H)

HPLCMS (Method B): [m/z]: 408.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(1H-imidazol-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 95)

In a similar fashion to general procedure 2, 4M HCl in dioxane (1 ml, 4mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-(2-{4-[(1H-imidazol-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(64) (61 mg, 0.13 mmol) in dioxane (4 ml) at room temperature for 18 h,to afford the title compound (23 mg, 48%) as a yellow solid afterpurification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.19 (s, 1H), 11.77 (s, 1H), 8.61 (t,J=5.9 Hz, 1H), 8.14 (s, 1H), 7.49 (br s, 2H), 7.13 (dd, J=5.9, 2.8 Hz,2H), 7.00 (br s, 1H), 6.81 (br s, 1H), 4.48 (d, J=5.9 Hz, 2H), 3.97 (s,2H), 3.17 (d, J=6.2 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H)

HPLCMS (Method B): [m/z]: 382.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(morpholin-4-yl)pyridin-4-yl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 96)

In a similar fashion to general procedure 2, 4M HCl in dioxane (1 ml)was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[2-(morpholin-4-yl)pyridin-4-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(65) (108 mg, 0.19 mmol) in dioxane (4 ml) at room temperature for 15 h,to afford the title compound (46 mg, 51%) as an orange solid afterpurification by neutral prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.90 (t, J=6.3 Hz, 1H), 8.15 (s, 1H),8.03 (d, J=5.1 Hz, 1H), 7.50 (dd, J=5.7, 3.3 Hz, 2H), 7.14 (dq, J=7.1,3.9 Hz, 2H), 6.73 (s, 1H), 6.61 (d, J=5.1 Hz, 1H), 4.38 (d, J=6.3 Hz,2H), 4.15 (d, J=29.7 Hz, 1H), 4.05 (s, 2H), 3.72-3.62 (m, 4H), 3.23 (t,J=6.8 Hz, 2H), 3.18 (s, 2H) 3.07 (t, J=6.8 Hz, 2H)

HPLCMS (Method B): [m/z]: 478.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(5-methylpyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 97)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.24 ml,0.96 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(5-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(66) (48 mg, 0.095 mmol) in dioxane (2 ml) at room temperature for 12 hto afford the title compound (10 mg, 26%) as a colourless oil afterpurification by neutral prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.31 (s, 1H), 8.10 (s, 1H), 7.60(dd, J=8.0, 1.8 Hz, 1H), 7.52 (dd, J=6.0, 3.1 Hz, 2H), 7.29 (d, J=8.0Hz, 1H), 7.22 (dd, J=6.0, 3.1 Hz, 2H), 4.65 (s, 2H), 4.10 (s, 2H), 3.28(t, J=6.6 Hz, 2H), 3.13 (t, J=6.6 Hz, 2H), 2.33 (s, 3H)

HPLCMS (Method D): [m/z]: 407.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[6-(dimethylamino)pyridin-3-yl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 98)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.17 ml,0.68 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[6-(dimethylamino)pyridin-3-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(67) (36 mg, 0.07 mmol) in dioxane (2 ml) at room temperature for 12 hto afford the title compound (8 mg, 27%) as a colourless oil afterpurification by neutral prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.07 (s, 1H), 8.05 (d, J=2.1 Hz,1H), 7.57-7.50 (m, 3H), 7.26-7.20 (m, 2H), 6.61 (d, J=8.8 Hz, 1H), 4.43(s, 2H), 4.07 (s, 2H), 3.24 (t, J=6.6 Hz, 2H), 3.10 (t, J=6.6 Hz, 2H),3.06 (s, 6H)

HPLCMS (Method B): [m/z]: 436.3 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-methylpyridin-4-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 99)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.18 ml,0.72 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-methylpyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(68) (36 mg, 0.07 mmol) in dioxane (2 ml) at room temperature for 12 hto afford the title compound (20 mg, 69%) as a colourless oil afterpurification by neutral prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.31 (d, J=5.3 Hz, 1H), 8.11 (s,1H), 7.52 (dd, J=5.9, 3.2 Hz, 2H), 7.30-7.13 (m, 4H), 4.58 (s, 2H), 4.09(s, 2H), 3.28 (t, J=6.6 Hz, 2H), 3.13 (t, J=6.6 Hz, 2H), 2.49 (s, 3H)

HPLCMS (Method B): [m/z]: 407.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 100)

In a similar fashion to general procedure 2, 4M HCl in dioxane (0.36 ml,1.44 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(1,5-dimethyl-1H-pyrazol-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(69) (74 mg, 0.15 mmol) in dioxane (2 ml) at room temperature for 12 h,to afford the title compound (19 mg, 33%) as a colourless oil afterpurification by neutral prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.05 (s, 1H), 7.53 (dd, J=5.8, 3.2Hz, 2H), 7.38 (s, 1H), 7.30-7.17 (m, 2H), 4.38 (s, 2H), 4.07 (s, 2H),3.74 (s, 3H), 3.23 (t, J=6.7 Hz, 2H), 3.09 (t, J=6.7 Hz, 2H), 2.29 (s,3H)

HPLCMS (Method D): [m/z]: 410.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 101)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-{2-[4-({[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(70) (216 mg, 0.163 mmol, 45% purity) and 12M HCl (2.1 ml) in MeOH (2.1ml) at 50° C. for 2 h gave the title compound (67 mg, 80%) as a whitesolid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 8.91-8.86 (m, 1H), 8.77(t, J=5.6 Hz, 1H), 8.45 (d, J=1.5 Hz, 1H), 8.14 (s, 1H), 7.59-7.35 (m,2H), 7.19-7.05 (m, 2H), 4.75 (d, J=5.6 Hz, 2H), 3.97 (s, 2H), 3.20 (t,J=6.8 Hz, 2H), 2.99 (t, J=6.8 Hz, 2H)

HPLCMS (Method D): [m/z]: 495.0 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloro-5-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound No. 102)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-chloro-5-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(71) (157 mg, 76%, 62% purity) and 12 M HCl (1.6 ml) in MeOH (1.6 ml) at50° C. for 2 h gave the title compound (50 mg, 62%) as a white solidafter purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.67 (t, J=5.6 Hz, 1H),8.54 (d, J=2.5 Hz, 1H), 8.14 (s, 1H), 8.11 (dd, J=8.5, 2.5 Hz, 1H),7.60-7.36 (m, 2H), 7.12 (d, J=4.7 Hz, 2H), 4.64 (d, J=5.1 Hz, 2H), 3.97(s, 2H), 3.19 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H)

HPLCMS (Method D): [m/z]: 445.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-fluoropyridin-3-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound No. 103)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-fluoropyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(72) (127 mg, 0.249 mmol) and 4M HCl in dioxane (0.622 ml, 2.487 mmol)in dioxane (4.4 ml) at room temperature for 5 h gave the title compound(26 mg, 25%) as a yellow solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.94 (t, J=6.2 Hz, 1H), 8.17 (s, 1H),8.13-8.09 (m, 1H), 7.85-7.79 (m, 1H), 7.55-7.46 (m, 2H), 7.32-7.28 (m,1H), 7.18-7.12 (m, 2H), 4.47 (d, J=6.1 Hz, 2H), 4.11-4.08 (m, 2H),3.27-3.23 (m, 2H), 3.15-3.08 (br m, 2H)

HPLCMS (Method F): [m/z]: 411.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-methoxypyridin-4-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 104)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(2-methoxypyridin-4-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(73) (104 mg, 0.199 mmol, 96% purity) and 12M HCl (1 ml) in MeOH (1 ml)at 5° C. for 2 h gave the title compound (35 mg, 42%) as a pale yellowsolid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.95 (t, J=6.3 Hz, 1H),8.13 (s, 1H), 8.06 (d, J=5.3 Hz, 1H), 7.58-7.38 (m, 2H), 7.17-7.07 (m,2H), 6.89 (dd, J=5.3, 1.1 Hz, 1H), 6.65 (s, 1H), 4.40 (d, J=6.3 Hz, 2H),3.96 (s, 2H), 3.81 (s, 3H), 3.19 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz,2H)

HPLCMS (Method B): [m/z]: 423.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(4,6-dimethylpyridin-3-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 105)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4,6-dimethylpyridin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(74) (0.077 g, 0.148 mmol) and 12M HCl (0.287 ml, 3.449 mmol) in MeOH (5ml) at 45° C. for 20 h gave the title compound (25 mg, 40%) as a yellowsolid after purification by neutral prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.73 (t, J=6.1 Hz, 1H), 8.25 (s, 1H),8.11 (s, 1H), 7.56-7.37 (br m, 2H), 7.16-7.09 (m, 2H), 7.02 (s, 1H),4.42 (d, J=6.0 Hz, 2H), 3.95 (s, 2H), 3.16 (t, J=6.5 Hz, 5H), 2.96 (t,J=6.8 Hz, 2H), 2.37 (s, 3H), 2.28 (s, 3H)

HPLCMS (Method G): [m/z]: 421.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(4-methylpyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 106)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(4-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(75) (90 mg, 0.178 mmol) and 12M HCl (0.345 ml, 4.143 mmol) in MeOH (5ml) at 45° C. for 20 h gave the title compound (21 mg, 29%) as a yellowsolid after purification by neutral prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.82 (t, J=6.0 Hz, 1H), 8.34 (d, J=5.0Hz, 1H), 8.14 (s, 1H), 7.57-7.39 (m, 2H), 7.14-7.10 (m, 3H), 7.09 (d,J=5.1 Hz, 1H), 4.52 (d, J=6.0 Hz, 2H), 3.97 (s, 2H), 3.19 (t, J=6.8 Hz,3H), 3.01-2.96 (m, 2H), 2.27 (s, 3H)

HPLCMS (Method G): [m/z]: 407.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 108)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(77) (112 mg, 0.21 mmol) and 4M HCl in dioxane (0.53 ml, 2.119 mmol) indioxane (2 ml) at room temperature for 16 h gave the title compound(36.7 mg, 40%) as a colourless oil after purification by neutralprep-HPLC.

1H-NMR (Methanol-d₄, 500 MHz): d[ppm]=8.27 (d, J=2.3 Hz, 1H), 8.09 (s,1H), 7.61-7.55 (m, 1H), 7.54-7.49 (m, 2H), 7.25-7.16 (m, 2H), 4.74 (s,2H), 4.10 (s, 2H), 3.28 (t, J=6.6 Hz, 2H), 3.14 (t, J=6.6 Hz, 2H)

HPLCMS (Method B): [m/z]: 429.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[3-(hydroxymethyl)pyridin-2-yl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 110)

In a similar fashion to general procedure 2, 4M HCl in dioxane (3.28 ml,13.13 mmol) was added to a solution of tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-{[(tert-butyldimethylsilyl)oxy]methyl}pyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(78) (191.5 mg, 0.09 mmol, 30% purity) in dioxane (2 ml) at roomtemperature for 15 h to give the title compound (8.9 mg, 23.5%) as ayellow oil after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.21 (s, 1H), 8.75 (t, J=5.0 Hz, 1H),8.40 (dd, J=4.8, 1.4 Hz, 1H), 8.14 (s, 1H), 7.81-7.77 (m, 1H), 7.57-7.40(br m, 2H), 7.31 (dd, J=7.6, 4.8 Hz, 1H), 7.14-7.10 (m, 2H), 5.41 (br s,1H), 4.63-4.59 (m, 4H), 3.97 (s, 2H), 3.20 (t, J=6.8 Hz, 2H), 2.98 (t,J=6.8 Hz, 2H)

HPLCMS (Method B): [m/z]: 422.2 [M+H]⁺

General Scheme 2 Above2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylicacid (80)

In a similar fashion to general procedure 5, LiOH (0.142 g, 5.92 mmol)and tert-butyl2-({[(tert-butoxy)carbonyl]({2-[4-(methoxycarbonyl)-1,3-thiazol-2-yl]ethyl})amino}methyl)-1H-1,3-benzodiazole-1-carboxylate(7) (1.12 g) in THF/Water (50 ml/10 ml) was stirred at room temperaturefor 16 h. The reaction mixture was acidified to pH 1-2 using saturatedKHSO₄ solution and then concentrated in vacuo. The crude residue wastriturated with DCM/IPA followed by MeOH/EtOAc to give the titlecompound (1.2 g, 50% purity) as a cream solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.39 (s, 1H), 7.96-7.91 (m, 2H),7.71-7.76 (m, 2H), 5.07 (s, 2H), 3.84 (t, J=6.3 Hz, 2H), 3.64 (t, J=6.3Hz, 2H)

HPLCMS (Method A): [m/z]: 303.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{[2-(morpholin-4-yl)phenyl]methyl}-1,3-thiazole-4-carboxamide(Example Compound No. 63)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylicacid (80) (200 mg, 0.66 mmol, 50% purity),1-[2-(morpholin-4-yl)phenyl]methanamine (127 mg, 0.66 mmol), DIPEA (0.35ml, 1.98 mmol) and HATU (377 mg, 0.99 mmol) in DMF (5 ml) afforded thetitle compound (37 mg, 12%) as a yellow solid after purification bybasic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.06 (s, 1H), 7.50 (dd, J=5.9, 3.2Hz, 2H), 7.27 (t, J=8.0 Hz, 2H), 7.24-7.18 (m, 2H), 7.16 (d, J=7.6 Hz,1H), 7.06 (t, J=7.6 Hz, 1H), 4.67 (s, 2H), 4.05 (s, 2H), 3.88-3.80 (m,4H), 3.23 (t, J=6.8 Hz, 2H), 3.07 (t, J=6.8 Hz, 2H), 2.90-2.84 (m, 4H)

HPLCMS (Method B): [m/z]: 477.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(1-methyl-1H-imidazol-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 64)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylicacid (80) (200 mg, 0.33 mmol, 50% purity),1-(1-methyl-1H-imidazol-2-yl)methanamine (36 mg, 0.33 mmol), DIPEA (230μl, 1.32 mmol) and HATU (189 mg, 0.496 mmol) in DCM (5 ml) and DMF (1ml) afforded the title compound (15 mg, 12%) after purification by basicprep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.09 (s, 1H), 7.53 (dd, J=5.9, 3.2Hz, 2H), 7.26-7.20 (m, 2H), 7.03 (d, J=1.1 Hz, 1H), 6.89 (d, J=1.2 Hz,1H), 4.66 (s, 2H), 4.08 (s, 2H), 3.73 (s, 3H), 3.25 (t, J=6.7 Hz, 2H),3.11 (t, J=6.7 Hz, 2H)

HPLCMS (Method B): [m/z]: 396.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(2-fluorophenyl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 65)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxylicacid (80) (200 mg, 0.53 mmol, 50% purity), 1-(2-fluorophenyl)methanamine(66 mg, 0.53 mmol), DIPEA (369 μl, 2.12 mmol) and HATU (302 mg, 0.79mmol) in DMF (2 ml) afforded the title compound (13 mg, 6%) as a whitesolid after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.09 (s, 1H), 7.53 (dd, J=5.9, 3.2Hz, 2H), 7.40-7.35 (m, 1H), 7.32-7.26 (m, 1H), 7.25-7.19 (m, 2H),7.15-7.05 (m, 2H), 4.64 (s, 2H), 4.08 (s, 2H), 3.26 (t, J=6.7 Hz, 2H),3.11 (t, J=6.7 Hz, 2H)

HPLCMS (Method D): [m/z]: 410.2 [M+H]⁺

General Scheme 4 Above2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87)

In a similar fashion to general procedure 5, ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (1)(8 g, 26.63 mmol) and LiOH (1.91 g, 79.90 mmol) in THF/water (200 ml/70ml) at room temperature for 20 h, gave the title compound (10.16 g,99.7%) as a yellow oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.32 (s, 1H), 6.99 (s, 1H), 3.28 (t,J=6.9 Hz, 2H overlapping with solvent), 3.10 (t, J=6.9 Hz, 2H), 1.36 (s,9H)

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.24 (s, 1H), 3.46 (t, J=6.6 Hz,2H), 3.19 (t, J=6.6 Hz, 2H), 1.41 (s, 9H)

HPLCMS (Method A): [m/z]: 294.9 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylicacid (88)

In a similar fashion to general procedure 5, methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylate(3) (769 mg, 2.56 mmol) and LiOH (310 mg, 13 mmol) in THF/water (20ml/20 ml) afforded the title compound (681 mg, 88%) as a yellow oil.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=12.76 (s, 1H), 6.99 (t, J=5.6 Hz, 1H),3.30-3.19 (m, 2H), 3.01 (t, J=6.9 Hz, 2H), 2.65 (s, 3H), 1.37 (s, 9H)

HPLCMS (Method A): [m/z]: 301.05 [M+H]⁺

2-(3-{[(Tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylicacid (89)

In a similar fashion to general procedure 5, ethyl2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylate(4) (726 mg, 2.31 mmol) and LiOH (166 mg, 6.93 mmol) in THF (12 ml) andwater (4 ml) afforded the crude title compound (791 mg) as a yellow oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.13 (s, 1H), 6.91 (t, J=5.0 Hz, 1H),3.05-2.93 (m, 4H), 1.83 (p, J=7.2 Hz, 2H), 1.38 (s, 9H)

HPLCMS (Method A): [m/z]: 285 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(90)

In a similar fashion to general procedure 6,(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (8.03 g, 40.35mmol),2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (10.2 g, 26.9 mmol), DIPEA (28.1 ml, 161.4 mmol) and HATU (12.3 g,32.3 mmol) in THF (300 ml) at room temperature for 2 h, gave the titlecompound (13.27 g) as an orange oil after purification by flash columnchromatography (eluting with a gradient of 20-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.70 (t, J=5.6 Hz, 1H), 8.39 (d, J=4.6Hz, 1H), 8.15 (s, 1H), 7.73-7.67 (m, 1H), 7.40 (dt, J=8.5, 4.4 Hz, 1H),7.04 (s, 1H), 4.65 (d, J=5.6 Hz, 2H), 3.31 (t, J=6.8 Hz, 2H, overlappingwith NMR solvent), 3.13 (t, J=6.8 Hz, 2H), 1.36 (s, 9H)

HPLCMS (Method A): [m/z]: 381 [M+H]⁺

Tert-butyl N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(91)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (4.09 g, 15.0 mmol), benzylamine (1.8 ml, 16.5 mmol), DIPEA (7.9ml, 45.1 mmol) and HATU (8.570 g, 22.5 mmol) in DCM (205 ml) affordedthe title compound (3.38 g, 56%, 90% purity) as a yellow oil afterpurification by flash column chromatography (eluting with a gradient of20-100% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.03 (s, 1H), 7.61 (s, 1H), 7.39-7.32(m, 4H), 7.31-7.27 (m, 1H), 4.64 (d, J=6.1 Hz, 2H), 3.54 (d, J=6.4 Hz,2H), 3.17 (t, J=6.4 Hz, 2H), 1.42 (s, 9H)

HPLCMS (Method E): [m/z]: 384 [M+Na]⁺

Tert-butylN-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(92)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (0.500 g, 1.836 mmol), 1-(pyridin-2-yl)methanamine (0.199 g, 1.836mmol), HATU (1.047 g, 2.754 mmol) and DIPEA (0.959 ml, 5.508 mmol) inDCM (25 ml) gave the title compound (0.905 g, quant.) as a yellow oilafter purification by flash chromatography (using a gradient of 20%heptane:80% ethyl acetate to 100% ethyl acetate).

HPLCMS (Method A): [m/z]: 363.05 [M+H]⁺

Tert-butylN-(2-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(93)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (0.7 g, 2.57 mmol), pyridazin-3-ylmethanamine (0.42 g, 3.86 mmol),DIPEA (2.24 ml, 12.85 mmol) and HATU (1.47 g, 3.86 mmol) in DMF (15 ml)afforded the title compound (0.919 g, 98%) as a brown oil afterpurification by flash column chromatography (eluting with a gradient of0-5% MeOH-DCM).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=9.21 (d, J=4.0 Hz, 1H), 8.41-8.32 (br m,1H), 8.03 (s, 1H), 7.91-7.85 (br m, 1H), 7.77-7.69 (br m, 1H), 5.01 (d,J=5.7 Hz, 2H), 4.96 (br s, 1H), 3.65-3.46 (m, 2H), 3.20 (t, J=6.2 Hz,2H), 1.42 (s, 9H)

HPLCMS (Method A): [m/z]: 364.05 [M+H]⁺

Tert-butylN-[2-(4-{[(6-methylpyridazin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(94)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (1.3 g, 4.15 mmol), (6-methylpyridazin-3-yl)methanaminehydrochloride (0.8 g, 5.01 mmol), DIPEA (2.89 ml, 16.61 mmol) and HATU(1.90 g, 5.01 mmol) in THF (35 ml) and DMF (5 ml) gave the titlecompound (0.878 g, 45%) as a colourless oil after purification by flashcolumn chromatography (kp-NH, eluting with a gradient of 0-15%MeOH/EtOAc) followed by a second flash column chromatography (kp-NH,eluting with a gradient of 70-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.04 (t, J=6.0 Hz, 1H), 8.17 (s, 1H),7.50 (q, J=8.6 Hz, 2H), 7.05 (s, 1H), 4.71 (d, J=6.1 Hz, 2H), 3.13 (t,J=6.8 Hz, 2H), 2.59 (s, 3H), 1.36 (s, 9H)

HPLCMS (Method A): [m/z]: 378.05 [M+H]⁺

Tert-butylN-(2-{4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(95)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (0.7 g, 2.57 mmol), pyrimidin-2-ylmethanamine (0.42 g, 3.86 mmol),DIPEA (2.24 ml, 12.85 mmol) and HATU (1.47 g, 3.86 mmol) in DMF (15 ml)afforded the title compound (0.545 g, 58%) as a pale yellow solid afterpurification by flash column chromatography (eluting with a gradient of0-5% MeOH/DCM).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.83 (s, 1H), 8.81 (s, 1H), 8.46 (br s,1H), 8.06 (s, 1H), 7.32 (app t, J=4.8 Hz, 1H), 5.01 (br s, 1H), 4.97 (d,J=5.3 Hz, 2H), 3.67-3.56 (m, 2H), 3.26 (t, J=6.4 Hz, 2H), 1.47 (s, 9H)

HPLCMS (Method A): [m/z]: 364.05 [M+H]⁺

Tert-butylN-[2-(4-{[(5-methylpyrimidin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(96)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (500 mg, 1.6 mmol, 87% purity), (5-methylpyrimidin-2-yl)methanamine(295 mg, 2.4 mmol), DIPEA (1.39 ml, 7.99 mmol) and HATU (911 mg, 2.4mmol) in THF (15 ml) and DMF (3 ml) afforded the crude title compound(600 mg, 85%, 85% purity) as a yellow oil after flash chromatography(eluting with a gradient of 0-80% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 378.10 [M+H]⁺

Tert-butylN-{2-[4-({5H,6H,7H-cyclopenta[b]pyridine-7-yl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(97)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (1.2 g, 4.41 mmol), 5H,6H,7H-cyclopenta[b]pyridin-7-aminehydrochloride (1.13 g, 6.61 mmol), DIPEA (2.3 ml, 13.22 mmol) and HATU(2.51 g, 6.61 mmol) in DMF (24 ml) afforded the title compound (1.53 g,85%) as a pale pink powder after purification by flash columnchromatography (eluting with a gradient of 0-5% MeOH/DCM).

HPLCMS (Method A): [m/z]: 389.15 [M+H]⁺

Tert-butylN-[2-(4-{[(3-methoxypyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(98)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (250 mg, 0.918 mmol), (3-methoxypyridin-2-yl)methanaminedihydrochloride (213 mg, 1.01 mmol), DIPEA (0.80 ml, 4.59 mmol) and HATU(524 mg, 1.38 mmol) in DCM (15 ml) afforded the crude title compound(417 mg) as a yellow oil after flash column chromatography (eluting witha gradient of 30-100% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.68 (s, 1H), 8.21 (d, J=4.7 Hz, 1H),8.02 (s, 1H), 7.21 (dd, J=8.2, 4.7 Hz, 1H), 7.16 (d, J=8.3 Hz, 1H), 5.02(s, 1H), 4.76 (d, J=4.7 Hz, 2H), 3.89 (s, 3H), 3.63 (d, J=6.0 Hz, 2H),3.23 (t, J=6.0 Hz, 2H), 1.44 (s, 9H)

HPLCMS (Method A): [m/z]: 393.40 [M+H]⁺

Tert-butylN-[2-(4-{[(3-methoxypyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(99)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylic acid(87) (250 mg, 0.918 mmol), 1-(1H-benzimidazol-2-yl)methanamine (149 mg,1.01 mmol), DIPEA (0.48 ml, 2.75 mmol) and HATU (524 mg, 1.38 mmol) inDCM (15 ml) afforded the crude title compound (0.709 mg, quantitative,81% purity) as a yellow oil after purification by flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM).

HPLCMS (Method A): [m/z]: 402 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1,3-thiazol-2-yl)ethyl]carbamate(100)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylicacid (88) (680 mg, 2.37 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (615 mg, 3.09 mmol), TEA (1.16 ml, 8.0 mmol) andHATU (1350 mg, 3.56 mmol) in DCM (30 ml) afforded the title compound(824 mg, 85%) as a yellow oil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.45 (m, 2H), 7.42 (ddd, J=9.4, 8.3, 1.2Hz, 1H), 7.30-7.24 (m, 1H), 4.99 (s, 1H), 4.83 (dd, J=5.2, 1.5 Hz, 2H),3.59 (d, J=6.0 Hz, 2H), 3.13 (t, J=6.0 Hz, 2H), 2.83 (s, 3H), 1.46 (s,9H)

HPLCMS (Method A): [m/z]: 395.15 [M+H]⁺

Tert-butylN-(2-{5-methyl-4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(101)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-thiazole-4-carboxylicacid (88) (0.315 g, 0.912 mmol), 1-(pyrimidin-2-yl)methanamine (0.119 g,1.094 mmol), THF (7 ml), DMF (1 ml), DIPEA (0.318 ml, 1.824 mmol) andHATU (0.416 g, 1.094 mmol) gave the title compound (0.134 g, 27%) as acolourless oil after purification by flash column chromatography (with agradient of 30-100% EtOAc in heptane).

HPLCMS (Method A): [m/z]: 378.10 [M+H]⁺

Tert-butylN-[3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)propyl]carbamate(102)

In a similar fashion to general procedure 6,2-(3-{[(tert-butoxy)carbonyl]amino}propyl)-1,3-thiazole-4-carboxylicacid (89) (661 mg, 2.31 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (689 mg, 3.46 mmol), DIPEA (2.41 ml, 13.85 mmol)and HATU (1053 mg, 2.77 mmol) in DMF (4 ml) and THF (4 ml) afforded thetitle compound (914 mg, 93%, 93% purity) as a yellow oil afterpurification by flash chromatography (eluting with a gradient of 20-100%EtOAc/heptane).

HPLCMS (Method A): [m/z]: 395.05 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103)

In a similar fashion to general procedure 2, 12M HCl (35.3 ml) andtert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(90) (13.3 g, 28.25 mmol) in MeOH (250 ml) were stirred at 50° C. for 3h. The mixture was concentrated in vacuo to give the title compound(12.8 g) as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.98 (s, 1H), 8.39 (d, J=4.7 Hz, 1H),8.21 (s, 1H), 8.17 (s, 3H), 7.72 (t, J=9.3 Hz, 1H), 7.42 (dt, J=8.5, 4.4Hz, 1H), 4.67 (d, J=5.8 Hz, 2H), 3.38 (t, J=6.5 Hz, 2H), 3.30-3.25 (m,2H)

HPLCMS (Method A): [m/z]: 280.9 [M+H]⁺

2-(2-Aminoethyl)-N-benzyl-1,3-thiazole-4-carboxamide hydrochloride (104)

In a similar fashion to general procedure 2, 12M HCl (2.5 ml) andtert-butyl N-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(91) (456 mg, 1.29 mmol) in MeOH (4.5 ml) at room temperature for 4 hgave the title compound (336 mg, 100%) as a beige solid. The product wasused in subsequent reactions without purification.

HPLCMS (Method E): [m/z]: 261.95 [M+H]⁺

2-(2-Aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (105)

In a similar fashion to general procedure 2, tert-butylN-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(92) (0.905 g, 2.50 mmol), 12M HCl (4.852 ml, 58.23 mmol) in MeOH (9 ml)gave the title compound (0.840 g, quant.) as a white solid.

HPLCMS (Method A): [m/z]: 262.95 [M+H]⁺

2-(2-Aminoethyl)-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (106)

In a similar fashion to general procedure 2, tert-butylN-(2-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(93) (0.919 g, 2.53 mmol) and 12M HCl (4.22 ml) in MeOH (15 ml) at roomtemperature for 16 h gave the title compound (0.840 g, 97%) as a brownresidue.

1H-NMR (Deuterium Oxide, 500 MHz): d[ppm]=9.17 (dd, J=4.9, 1.5 Hz, 1H),8.12 (s, 1H), 8.03 (dd, J=8.6, 1.5 Hz, 1H), 7.99 (dd, J=8.6, 4.9 Hz,1H), 4.86 (s, 2H), 3.45-3.39 (m, 2H), 3.48-3.43 (m, 2H)

HPLCMS (Method A): [m/z]: 263.95 [M+H]⁺

2-(2-Aminoethyl)-N-[(6-methylpyridazin-3-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (107)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(6-methylpyridazin-3-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(94) (878 mg, 1.86 mmol) and 12M HCl (3.10 ml) in MeOH (15 ml) at roomtemperature for 24 h, gave the title compound (764 mg, quant.) as anoff-white solid. The product was used in subsequent reactions withoutpurification.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.49 (d, J=8.9 Hz, 1H), 8.41 (d, J=8.9Hz, 1H), 8.26 (s, 1H), 4.97 (s, 2H), 3.53-3.47 (m, 4H), 2.91 (s, 3H)

HPLCMS (Method A): [m/z]: 277.95 [M+H]⁺

2-(2-Aminoethyl)-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (108)

In a similar fashion to general procedure 2, tert-butylN-(2-{4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(95) (0.545 g, 1.499 mmol) and 12M HCl (4.22 ml) in MeOH (15 ml) at roomtemperature for 16 h gave the title compound (0.530 g, quant.) as a paleyellow foam.

1H-NMR (Deuterium Oxide, 500 MHz): d[ppm]=8.73 (d, J=5.1 Hz, 2H), 8.16(s, 1H), 7.47 (app t, J=5.1 Hz, 1H), 4.80 (s, 2H), 3.51-3.46 (m, 2H),3.45-3.41 (m, 2H)

HPLCMS (ESI+): [m/z]: 263.95 [M+H]⁺ as the freebase (METCR1673 Generic 2min)2-(2-Aminoethyl)-N-[(ethythypyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamide(109)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(5-methylpyrimidin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(96) (600 mg, 1.59 mmol) and 12 M HCl (2.65 ml) in MeOH (10 ml) affordedthe title compound freebase (283 mg, 44%) as a white solid afterpurification by flash chromatography (eluting with a gradient of 0-10% 7M ammonia in MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.77-8.70 (m, 1H), 8.62 (s, 2H), 8.14(s, 1H), 4.64 (d, J=4.0 Hz, 2H), 3.13 (t, J=6.6 Hz, 2H), 3.02 (t, J=6.6Hz, 2H), 2.26 (s, 3H)

HPLCMS (Method A): [m/z]: 278.2 [M+H]⁺

2-(2-Aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridine-7-yl}-1,3-thiazole-4-carboxamidedihydrochloride (110)

In a similar fashion to general procedure 2, 4M HCl in dioxane (14.45ml, 57.8 mmol) was added to an ice-cold solution of tert-butylN-{2-[4-({5H, 6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol-2-yl]ethyl}carbamate(97) (1.53 g, 3.94 mmol) in MeOH (5 ml). The mixture was stirred at roomtemperature for 2 h. The title compound (1.32 g, 93%) was isolated byfiltration after precipitation from Et₂O (5 ml).

HPLCMS (Method A): [m/z]: 289.05 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-methoxypyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(111)

In a similar fashion to general procedure 2, 12M HCl (2.5 ml) and crudetert-butylN-[2-(4-{[(3-methoxypyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(98) (417 mg) in MeOH (5 ml) at room temperature for 2 h, gave the titlecompound (125 mg) as a white solid after purification by flash columnchromatography (kp-NH, eluting with a gradient of 0-10% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.59 (s, 1H), 8.15-8.11 (m, 2H), 7.44(d, J=8.3 Hz, 1H), 7.33 (dd, J=8.3, 4.7 Hz, 1H), 4.57 (d, J=5.2 Hz, 2H),3.88 (s, 3H), 3.08 (t, J=6.6 Hz, 2H), 2.94 (t, J=6.6 Hz, 2H), 2.69 (s,2H)

HPLCMS (Method A): [m/z]: 292.95 [M+H]⁺

2-(2-Aminoethyl)-N-(1H-1,3-benzodiazol-2-ylmethyl)-1,3-thiazole-4-carboxamide(112)

In a similar fashion to general procedure 2, 12M HCl (2.5 ml) and crudetert-butylN-(2-{4-[(1H-1,3-benzodiazol-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(99) (709 mg, 1.43 mmol, 81% purity) in MeOH (5 ml) at room temperaturefor 2 h, gave the title compound (111 mg, 25%) as a brown solid afterpurification by flash column chromatography (kp-NH, eluting with agradient of 0-10% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.88 (s, 1H), 8.17 (s, 1H), 7.49 (s,2H), 7.13 (dd, J=6.0, 3.1 Hz, 2H), 4.68 (d, J=6.0 Hz, 2H), 3.08 (t,J=6.6 Hz, 2H), 2.95 (t, J=6.6 Hz, 2H)

HPLCMS (Method A): [m/z]: 301.95 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-thiazole-4-carboxamidedihydrochloride (113)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1,3-thiazol-2-yl)ethyl]carbamate(100) (823 mg, 2.09 mmol) and 12M HCl (3 ml) in MeOH (30 ml) affordedthe title compound (794 mg, quant.) as a tan solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.87 (t, J=5.9 Hz, 1H), 8.40 (dt,J=4.4, 1.3 Hz, 1H), 8.13 (s, 3H), 7.73 (ddd, J=9.9, 8.3, 1.2 Hz, 1H),7.43 (dt, J=8.5, 4.5 Hz, 1H), 4.69-4.60 (m, 2H), 3.32-3.19 (m, 4H), 2.71(s, 3H)

HPLCMS (Method A): [m/z]: 295.05 [M+H]⁺

2-(2-Aminoethyl)-5-methyl-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (114)

In a similar fashion to general procedure 2, tert-butylN-(2-{5-methyl-4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(101) (0.482 g, 0.795 mmol), MeOH (6 ml) and 12M HCl (1.325 ml, 15 0.90mmol) give the title compound (0.420 g, 99%) as a yellow solid

HPLCMS (Method A): [m/z]: 277.95 [M+H]⁺

2-(3-Aminopropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (115)

In a similar fashion to general procedure 2, 4M HCl in dioxane (2.89 ml,11.55 mol) and tert-butylN-[3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)propyl]carbamate(102) (0.91 g, 2.31 mmol) in dioxane (6 ml) and MeOH (2 ml) afforded thetitle compound (1.13 g, 85%, 64% purity) as a pale orange oil. Compoundwas used on the next step without purification.

HPLCMS (Method A): [m/z]: 295.00 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-methoxypyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 59)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-[(3-methoxypyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(111) (90 mg, 0.308 mmol) and 1H-benzimidazole-2-carbaldehyde (49 mg,0.339 mmol) in DCE (9 ml) at room temperature for 2 h, followed by theaddition of NaBH(OAc)₃ (91 mg, 0.431 mmol) gave the title compound (50mg, 38%) as a yellow solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 8.58 (t, J=5.2 Hz, 1H),8.14 (s, 1H), 8.09-8.06 (m, 1H), 7.59-7.40 (m, 3H), 7.31 (dd, J=8.3, 4.7Hz, 1H), 7.12 (d, J=3.5 Hz, 2H), 4.56 (d, J=5.2 Hz, 2H), 3.97 (s, 2H),3.87 (s, 3H), 3.20 (t, J=6.8 Hz, 2H), 2.98 (t, J=6.8 Hz, 2H)

HPLCMS (Method B): [m/z]: 423.2 [M+H]⁺

N-(1H-1,3-Benzodiazol-2-ylmethyl)-2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-1,3-thiazole-4-carboxamide(Example Compound No. 60)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-(1H-1,3-benzodiazol-2-ylmethyl)-1,3-thiazole-4-carboxamide(112) (111 mg, 0.368 mmol) and 1H-benzimidazole-2-carbaldehyde (59 mg,0.405 mmol) in DCE (12 ml) at room temperature for 2 h, followed byaddition of NaBH(OAc)₃ (109 mg, 0.516 mmol) gave the title compound (15mg, 9%) as a yellow solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.23 (s, 2H), 8.89 (t, J=5.9 Hz, 1H),8.18 (s, 1H), 7.49 (s, 4H), 7.13 (tt, J=7.0, 3.5 Hz, 4H), 4.69 (d, J=5.9Hz, 2H), 3.98 (s, 2H), 3.21 (t, J=6.8 Hz, 2H), 3.00 (t, J=6.8 Hz, 2H)

HPLCMS (Method B): [m/z]: 430.3 [M−H]⁺

2-(2-{[(6-Fluoro-1H-1,3-benzodiazol-2-yl)methyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 114)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (200 mg, 0.49 mmol),6-fluoro-1H-benzimidazole-2-carbaldehyde (89 mg, 0.539 mmol) and DIPEA(0.342 ml, 1.961 mmol) in MeOH (10 ml) at room temperature for 24 h,followed by addition of NaBH₄ (28 mg, 0.735 mmol) gave the titlecompound (83 mg, free base) as a brown solid after purification by basicprep-HPLC. The freebase and 12M HCl (1 ml) in MeOH (4 ml) were stirredat room temperature to give the title compound (111 mg, 42%) aftersolvent evaporation in vacuo.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.52 (s, 1H), 8.28 (s, 1H), 8.24(s, 1H), 7.86 (s, 1H), 7.78 (s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 4.97(s, 2H), 4.92 (s, 2H), 3.84 (s, 2H), 3.64 (t, J=6.1 Hz, 2H)

HPLCMS (Method D): [m/z]: 429.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-5-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound No. 139)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (400 mg, 0.64 mmol, 56% purity),1H-1,3-benzodiazole-5-carbaldehyde (112 mg, 0.77 mmol) and DIPEA (0.56ml, 3.19 mmol) in MeOH (10 ml) at room temperature for 18 h, followed bythe addition of NaBH₄ (36 mg, 0.96 mmol) gave the title compound (207mg, 75.9%) as a cream solid following purification by flash columnchromatography (KP—NH, eluting with a gradient of 0-20% MeOH/DCM).

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.31-8.29 (m, 1H), 8.14 (s, 1H),8.10 (s, 1H), 7.64-7.53 (m, 3H), 7.37-7.33 (m, 1H), 7.29 (dd, J=8.3, 1.3Hz, 1H), 4.79 (d, J=1.6 Hz, 2H), 3.96 (s, 2H), 3.28 (t, J=6.9 Hz, 2H),3.09 (t, J=6.9 Hz, 2H)

HPLCMS (Method C): [m/z]: 411.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-4-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound No. 140)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (400 mg, 0.64 mmol, 56.3% purity),1H-1,3-benzodiazole-4-carbaldehyde (112 mg, 0.77 mmol) and DIPEA (0.56ml, 3.19 mmol) in MeOH (10 ml) at room temperature for 18 h, followed bythe addition of NaBH₄ (36 mg, 0.96 mmol) gave the title compound (255mg, 96.4%) as an off-white solid after purification by flash columnchromatography (KP—NH, eluting with a gradient of 0-10% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.41 (s, 1H), 8.65 (t, J=5.5 Hz, 1H),8.39-8.36 (m, 1H), 8.17 (br s, 1H), 8.12 (br s, 1H), 7.72-7.67 (m, 1H),7.43-7.37 (m, 1H), 7.22-7.08 (m, 2H), 4.66 (dd, J=5.7, 1.4 Hz, 2H), 4.13(s, 1H), 4.04 (s, 1H), 3.18 (t, J=6.5 Hz, 2H), 2.97-2.87 (m, 2H)

HPLCMS (Method C): [m/z]: 411.2 [M+H]⁺

2-{3-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]propyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 134)

In a similar fashion to general procedure 3,2-(3-aminopropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (115) (150 mg, 0.261 mmol, 64% purity),1H-benzimidazole-2-carbaldehyde (46 mg, 0.314 mmol), DIPEA (0.18 ml,1.05 mmol) in MeOH (2 ml) at room temperature for 16 h, followed byaddition of NaBH₄ (15 mg, 0.39 mmol) afforded the freebase compound (53mg, 48%) as a colourless oil after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=12.16 (s, 1H), 8.66 (t, J=5.5 Hz, 1H),8.38 (dt, J=4.7, 1.4 Hz, 1H), 8.13 (s, 1H), 7.70 (ddd, J=10.0, 8.4, 1.2Hz, 1H), 7.61-7.27 (m, 2H), 7.11 (dd, J=6.0, 3.1 Hz, 2H), 4.65 (dd,J=5.5, 1.4 Hz, 2H), 3.91 (s, 2H), 3.09 (t, 2H), 2.64 (t, J=6.8 Hz, 2H),1.92 (m, 2H)

HPLCMS (Method D): [m/z]: 425.2 [M+H]⁺

The freebase (35 mg, 0.082 mmol) and 12M HCl (20 μL, 0.247 mmol) werestirred in MeOH (2 ml) at room temperature to afford the title compound(44 mg, quant.) as a white solid after the solvent was removed in vacuo.

1H-NMR (D₂O, 500 MHz): d[ppm]=8.50 (dd, J=5.4, 1.2 Hz, 1H), 8.19-8.12(m, 2H), 7.89-7.78 (m, 3H), 7.66 (dt, J=6.3, 3.3 Hz, 2H), 4.89 (s, 2H),4.85 (d, J=1.3 Hz, 2H), 3.46-3.39 (m, 2H), 3.26 (t, J=7.2 Hz, 2H), 2.33(m, 2H)

HPLCMS (Method D): [m/z]: 425.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-thiazole-4-carboxamide (Example CompoundNo. 164)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-thiazole-4-carboxamidedihydrochloride (113) (274 mg, 0.75 mmol),1H-1,3-benzodiazole-2-carbaldehyde (109 mg, 0.75 mmol), DIPEA (0.45 ml,2.61 mmol) and anhydrous MgSO₄ (200 mg) in MeOH (10 ml) and DCM (10 ml)at room temperature for 20 h, followed by addition of NaBH₄ (60 mg, 1.48mmol) afforded the title compound (140 mg, 44%) as a pale yellow solidafter purification by prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.59 (t, J=5.6 Hz, 1H),8.36 (dt, J=4.7, 1.4 Hz, 1H), 7.70 (ddd, J=9.9, 8.4, 1.1 Hz, 1H), 7.53(d, J=7.5 Hz, 1H), 7.44 (d, J=7.5 Hz, 1H), 7.40 (dt, J=8.5, 4.4 Hz, 1H),7.13 (p, J=6.6 Hz, 2H), 4.65-4.59 (m, 2H), 3.96 (s, 2H), 3.10 (t, J=6.8Hz, 2H), 2.94 (t, J=6.8 Hz, 2H), 2.68 (s, 3H)

HPLCMS (Method C): [m/z]: 425.2 [M+H]⁺

General Procedure 7:2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 94)

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (2.0 g, 3.96 mmol) was added to a solution of2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (1.12 g, 5.15 mmol)and DIPEA (10.6 ml, 59.45 mmol) in DMF (60 ml). The reaction mixture wasallowed to stir at 30° C. for 6 d (reaction was monitored by LCMS). Themixture was concentrated in vacuo and the residue was neutralised usingsat. NaHCO₃ (aq). The aqueous layer was extracted using 4:1 CHCl₃/IPA(4×100 ml) and the combined organic layers were dried (MgSO₄), filteredand evaporated in vacuo. The crude residue was purified by flash columnchromatography (kp-NH, eluting with a gradient of 60-100% EtOAc/heptanefollowed by 0-20% MeOH/EtOAc) follow by neutral reverse-phase columnchromatography (gradient elution 0-60% MeCN/water) to give the titlecompound (0.173 g, 10%) as a yellow oil.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.31 (d, J=4.6 Hz, 1H), 8.02 (s,1H), 7.57 (t, J=9.1 Hz, 1H), 7.45-7.40 (m, 2H), 7.36 (dd, J=8.6, 4.3 Hz,1H), 7.17 (dd, J=6.0, 3.2 Hz, 2H), 4.68 (s, 2H), 3.26 (d, J=6.8 Hz, 2H),3.15-3.07 (m, 6H)

HPLCMS (Method D): [m/z]: 425.1 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 94—HCl salt)

4M HCl in 1,4-dioxane (2.38 ml, 9.82 mmol) was added to a solution of2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 94) (1.30 g, 2.98 mmol) in MeOH (15 ml) and thereaction mixture was stirred at room temperature for 2 h. The mixturewas evaporated in vacuo to afford the title compound (1.16 g, 70%) as anoff-white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.48 (s, 1H), 8.25 (s, 1H), 8.07(s, 1H), 7.79 (dt, J=6.9, 3.4 Hz, 2H), 7.73 (s, 1H), 7.61 (dd, J=6.2,3.1 Hz, 2H), 4.91 (s, 2H), 3.82 (s, 4H), 3.75 (t, J=6.4 Hz, 2H), 3.61(t, J=6.4 Hz, 2H)

HPLCMS (Method D): [m/z]: 425.1 [M+H]⁺

Tert-butyl2-[({2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}amino)methyl]-5-methyl-1H-1,3-benzodiazole-1-carboxylate(116)

To a solution of 2-(2-aminoethyl)-N-benzyl-1,3-thiazole-4-carboxamide(104) (186 mg, 0.71 mmol) in DMF (5 ml) was added DIPEA (0.138 ml, 1mmol), followed by addition of tert-butyl2-(chloromethyl)-5-methyl-1H-1,3-benzodiazole-1-carboxylate (F) (200 mg,0.71 mmol) and the reaction heated at 90° C.

Upon completion (LCMS) the mixture was concentrated in vacuo. Residuewas purified by flash column chromatography (eluting with DCM/MeOH,95:5) as a yellow oil (85 mg, 24%).

1H-NMR (CDCl₃, 400 MHz): d[ppm]=7.95 (s, 1H), 7.61 (s, 1H), 7.31 (dd,J=24.4, 4.2 Hz, 6H), 7.07 (d, J=8.2 Hz, 1H), 4.61 (d, J=6.1 Hz, 2H),4.58 (s, 2H), 3.74 (t, J=6.6 Hz, 2H), 3.20 (t, J=6.6 Hz, 2H), 2.46 (s,3H), 1.36 (s, 9H),

HPLCMS (Method I): [m/z]: 506.6 [M+H]⁺

Tert-butyl2-[({2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]ethyl}amino)methyl]-5-methoxy-1H-1,3-benzodiazole-1-carboxylate(117) andN-benzyl-2-(2-{[(5-methoxy-1H-1,3-benzodiazol-2-yl)methyl]amino}ethyl)-1,3-thiazole-4-carboxamide(118)

In a similar fashion to general procedure 7,2-(2-aminoethyl)-N-benzyl-1,3-thiazole-4-carboxamide (104) (0.4 g, 2mmol), tert-butyl2-(chloromethyl)-5-methoxy-1H-1,3-benzodiazole-1-carboxylate (F) (0.45g, 2 mmol), DIPEA (0.4 g, 3 mmol) and NaI (0.23 g, 2 mmol) in MeCN (30ml) under argon at 90° C. for 18 h, gave a mixture of a red solid, (bocdeprotected product, 350 mg, 27%) and the expected product as a whitesolid (133 mg, 21%) after purification by flash column chromatography(eluting with a gradient DCM/MeOH 5-7%).

HPLCMS (Method I): [m/z]: 522.6 [M+H]⁺ and 422.6 [M+H]⁺

2-{2-[(1,3-Benzoxazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 115)

In a similar fashion to general procedure 7,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (300 mg, 0.735 mmol),2-(chloromethyl)-1,3-benzoxazole (160 mg, 0.956 mmol), DIPEA (1.922 ml,11.03 mmol) and DMF (15 ml) at 30° C. for 24 h, gave the title compound(102 mg, 34%) as a yellow oil after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.30 (d, J=4.7 Hz, 1H), 8.08 (s,1H), 7.66-7.62 (m, 1H), 7.60-7.54 (m, 2H), 7.39-7.32 (m, 3H), 4.77 (d,J=1.6 Hz, 2H), 4.14 (s, 2H), 3.27 (d, J=6.3 Hz, 2H), 3.18 (t, J=6.6 Hz,2H)

HPLCMS (Method D): [m/z]: 412.1 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 58)

In a similar fashion to general procedure 7,2-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (105) (240 mg, 0.72 mmol),2-(2-chloroethyl)-1H-1,3-benzodiazole (259 mg, 1.43 mmol) and DIPEA(2.17 ml, 12.53 mmol) in DMF (10 ml) afforded the title compound (64 mg,22%) as a brown solid after purification by basic prep-HPLC followed byflash column chromatography (eluting with a gradient of 0-10% MeOH/DCMfollowed by 0.8 M ammonia in MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.87 (t, J=6.0 Hz, 1H), 8.50 (d, J=4.6Hz, 1H), 8.10 (s, 1H), 7.74 (td, J=7.7, 1.7 Hz, 1H), 7.44 (s, 2H),7.33-7.21 (m, 2H), 7.10 (dd, J=5.9, 3.2 Hz, 2H), 4.55 (d, J=6.0 Hz, 2H),3.15 (t, J=6.7 Hz, 2H), 3.02 (t, J=6.7 Hz, 2H), 2.90-2.96 (m, 4H)

HPLCMS (Method G): [m/z]: 407.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl](methyl)amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 112)

2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 94) (114 mg, 0.205 mmol), Et₃N(0.143 ml, 1.025 mmol) and DMF (1 ml) were stirred at room temperaturefor 1 h. MeI (0.059 ml, 0.949 mmol) was added and stirred at roomtemperature for 140 h. Water (10 ml) was added and the solvent reducedin vacuo. The crude product was purified by basic prep-HPLC to give thefree base (18 mg). MeOH (2 ml) and 4 M HCl in dioxane (0.05 ml, 0.205mmol) were added and stirred at room temperature for 2 h. The reactionwas concentrated in vacuo to give the title compound (24 mg, 21%) as ayellow solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.48-8.39 (br m, 1H), 8.26 (s,1H), 8.02-7.84 (br m, 1H), 7.82-7.76 (m, 2H), 7.67-7.54 (m, 3H), 4.84(s, 2H, obscured by H₂O peak), 3.99-3.84 (m, 6H), 3.71 (t, J=6.8 Hz,2H), 3.16 (s, 3H)

HPLCMS (Method D): [m/z]: 439.1 [M+H]⁺

2-{2-[2-(1H-1, 3-Benzodiazol-2-yl)acetamido]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (ExampleCompound No. 113)

In a similar fashion to general procedure 6,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (150 mg, 0.368 mmol),2-(1H-1,3-Benzodiazol-2-yl)acetic acid (114 mg, 0.552 mmol), DIPEA(0.384 ml, 2.206 mmol) and HATU (210 mg, 0.52 mmol) in THF (20 ml) atroom temperature for 2 h, gave the freebase compound (73 mg) afterpurified by basic prep-HPLC. The freebase and 12M HCl (2 ml) in MeOH (6ml) were stirred at room temperature for 2 h. The reaction wasconcentrated in vacuo to give the title compound (97 mg, 51%) as a brownsolid.

¹H NMR (Methanol-d4, 500 MHz): d[ppm]=8.60 (dd, J=5.5, 1.2 Hz, 1H), 8.32(td, J=8.9, 1.1 Hz, 1H), 8.15 (s, 1H), 7.96-7.90 (m, 1H), 7.81-7.75 (m,2H), 7.63-7.58 (m, 2H), 4.93 (d, J=1.1 Hz, 2H), 4.27 (s, 2H), 3.76 (t,J=6.7 Hz, 2H), 3.32 (t, J=6.6 Hz, 2H)

HPLCMS (Method D): [m/z]: 439.1 [M+H]⁺

2-{2-[(Cyclopropylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4carboxamide (119)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (56% purity, 500 mg, 0.793 mmol),cyclopropanecarbaldehyde (67 mg, 0.951 mmol) and DIPEA (0.552 ml, 3.17mmol) in MeOH (7 ml) at room temperature for 16 h, followed by theaddition of NaBH₄ (45 mg, 1.19 mmol) gave the title compound (149 mg,51%) as a colourless oil after purification by flash columnchromatography (kp-NH, eluting with a gradient 0-10% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.65 (t, J=5.7 Hz, 1H), 8.39 (dt,J=4.5, 1.3 Hz, 1H), 8.12 (s, 1H), 7.71 (ddd, J=10.0, 8.3, 1.3 Hz, 1H),7.41 (dt, J=8.6, 4.5 Hz, 1H), 4.66 (dd, J=5.7, 1.4 Hz, 2H), 3.13 (t,J=6.7 Hz, 2H), 2.92 (t, J=6.7 Hz, 2H), 2.43 (d, J=6.6 Hz, 2H), 1.92 (s,1H), 0.93-0.81 (m, 1H), 0.43-0.35 (m, 2H), 0.13-0.06 (m, 2H)

HPLCMS (Method F): [m/z]: 335.8 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl](cyclopropylmethyl)amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 148)

In a similar fashion to general procedure 7,2-{2-[(cyclopropylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(119) (149 mg, 0.45 mmol), 2-(2-chloroethyl)-1H-1,3-benzodiazolehydrochloride (116 mg, 0.53 mmol) and DIPEA (0.4 ml, 2.23 mmol) at 30°C. for 32 h afforded the title compound (5 mg, 2%) as a yellow oil afterpurification by basic prep-HPLC followed by flash column chromatography(eluting with a gradient of 0-10% MeOH in DCM then 0-10% 7 M ammonia inMeOH/DCM).

1H-NMR (Acetone-d6, 500 MHz): d[ppm]=8.48 (s, 1H), 8.39 (d, J=4.7 Hz,1H), 7.98 (s, 1H), 7.66-7.54 (m, 1H), 7.49-7.33 (m, 3H), 7.10 (dd,J=6.0, 3.2 Hz, 2H), 4.75 (dd, J=5.3, 1.5 Hz, 2H), 3.33 (t, J=6.7 Hz,2H), 3.30-3.11 (m, 6H), 2.67 (d, J=6.7 Hz, 2H), 1.10-0.94 (m, 1H),0.60-0.43 (m, 2H), 0.26-0.22 (m, 2H)

HPLCMS (Method B): [m/z]: 479.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 122)

In a similar fashion using general procedure 7,2-(2-aminoethyl)-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (106) (409 mg, 1.22 mmol),2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (316.9 mg, 1.46mmol) and DIPEA (3.18 ml, 0.02 mol) in DMF (5 ml) at room temperaturefor 5 d gave the freebase product after purification by flash columnchromatography using a gradient elution of 0-20% MeOH/DCM followed byfurther purification by basic prep-HPLC.

The freebase product was re-dissolved in MeOH (5 ml) and treated with 12M HCl (1 ml) for 1 h to give the title compound (132 mg, 21%) as a paleyellow solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=9.52 (dd, J=5.2, 1.2 Hz, 1H), 8.59(dd, J=8.7, 1.2 Hz, 1H), 8.46 (dd, J=8.7, 5.2 Hz, 1H), 8.28 (s, 1H),7.83 (dd, J=6.2, 3.1 Hz, 2H), 7.65 (td, J=6.2, 5.5, 2.2 Hz, 2H), 5.04(s, 2H), 3.90-3.82 (m, J=4.2 Hz, 4H), 3.79 (t, J=6.4 Hz, 2H), 3.64 (t,J=6.4 Hz, 2H)

HPLCMS (Method C): [m/z]: 408.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 129)

In a similar fashion to general procedure 7,2-(2-aminoethyl)-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (108) (300 mg, 0.89 mmol),2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (193.7 mg, 0.89mmol) and DIPEA (3.11 ml, 17.8 mmol) in DMF (10 ml) at room temperaturefor 9 d gave the freebase product after purification by flash columnchromatography (eluting with a gradient of 0-40% MeOH/DCM) followed byfurther purification by basic prep-HPLC.

The freebase product was re-dissolved in MeOH (5 ml) and treated with12M HCl for 30 min to give the title compound (26 mg, 6%) as a paleyellow solid.

1H-NMR (D₂O, 500 MHz): d[ppm]=8.66 (d, J=5.1 Hz, 2H), 8.15 (s, 1H), 7.67(dt, J=6.7, 3.4 Hz, 2H), 7.53 (td, J=6.2, 5.5, 2.1 Hz, 2H), 7.40 (t,J=5.1 Hz, 1H), 4.60 (s, 2H), 3.76-3.65 (m, 6H), 3.54 (t, J=6.4 Hz, 2H)

HPLCMS (Method E): [m/z]: 408.1 [M+H]⁺

General Procedure 8:2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 155)

DBU (15.37 μl, 0.1 mmol) was added to a suspension of2-(2-aminoethyl)-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (109) (36 mg, 0.1 mmol) in MeCN (3 ml).N-(2-nitrophenyl)prop-2-enamide (D) (19 mg, 0.1 mmol) was added and thereaction mixture was stirred at room temperature overnight. The reactionwas diluted with EtOAc (5 ml) and washed with 10% NaHCO₃ (5 ml), water(5 ml), brine (5 ml), dried (MgSO4), filtered and evaporated to give acrude intermediate which was further reacted with iron powder (3 mg,0.05 mmol) in AcOH (3 ml) at 80° C. for 3 h. The reaction mixture wasdiluted with water (5 ml), then made basic by slow addition of 10M NaOH(aq). The mixture was then further diluted with water (10 ml) andextracted with 4:1 chloroform/IPA (4×30 ml). The combined organic layerswere separated, dried (MgSO₄) and evaporated under vacuum. The crudematerial was purified by basic prep-HPLC to give the title compound (8mg, 67%) as a colourless film.

1H-NMR (Acetone-d6, 500 MHz): d[ppm]=8.58 (s, 2H), 8.44 (s, 1H), 8.03(s, 1H), 7.45 (s, 2H), 7.14-7.05 (m, 2H), 4.72 (d, J=4.3 Hz, 2H), 3.24(t, J=6.5 Hz, 2H), 3.13 (m, 4H), 3.07 (t, J=6.2 Hz, 2H), 2.29 (s, 3H)

HPLCMS (Method C): [m/z]: 422.0 [M+H]⁺

N-{5H,6H,7H-Cyclopenta[b]pyridin-7-yl}-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxamide(Example Compound No. 158)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazole-4-carboxamidedihydrochloride (110) (660 mg, 1.83 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (344 mg, 1.79 mmol) and DBU (0.8 ml,5.37 mmol) in MeCN (8 ml) gave a crude intermediate which was furtherreacted with iron powder (180 mg, 3.22 mmol) in AcOH (10 ml) to affordthe title compound (176 mg, 25%) as a pale yellow foam afterpurification by flash column chromatography (eluting with a gradient of5-10% 3 M ammonia in MeOH/DCM) followed by basic prep-HPLC.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.27 (d, J=4.7 Hz, 1H), 8.17 (s, 1H),8.07 (br s, 1H), 7.43 (br s, 2H), 7.37-7.32 (m, 1H), 7.19 (dt, J=8.5,4.4 Hz, 1H), 7.15-7.11 (m, 2H), 4.73 (dd, J=5.0, 1.3 Hz, 2H), 3.18 (t,J=6.2 Hz, 2H), 3.17-3.08 (m, 4H), 3.04 (t, J=6.2 Hz, 2H)

HPLCMS (Method C): [m/z]: 433.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(6-methylpyridazin-3-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 174)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(6-methylpyridazin-3-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (107) (382 mg, 0.932 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (161 mg, 0.839 mmol) and DBU (0.300ml, 2.01 mmol) in MeCN (15 ml) at room temperature for 2 h gave therequired Michael intermediate (163 mg, 31%) as a yellow oil afterpurification by flash column chromatography (0-3% MeOH/DCM) followed bya second purification using an isolute silica column with a gradient of0-2% 7M NH₃/MeOH in DCM.

The Michael intermediate (163 mg, 0.288 mmol) was reacted with ironpowder (32 mg) in AcOH (3 ml) at 80° C. for 1 h to give the titlecompound (15 mg, 12%) as a beige solid after purification by basicprep-HPLC followed kp-NH silica column chromatography.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.00 (t, J=6.0 Hz, 1H), 8.10 (s, 1H),7.52-7.42 (m, 4H), 7.13-7.09 (m, 2H), 4.70 (d, J=6.1 Hz, 2H), 3.15 (t,J=6.7 Hz, 2H), 3.04-3.00 (m, 2H), 3.00-2.94 (m, 4H), 2.59 (s, 3H)

HPLCMS (Method B): [m/z]: 422.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-thiazole-4-carboxamide(Example Compound No. 165)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-thiazole-4-carboxamidedihydrochloride (113) (528 mg, 1.44 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (276 mg, 1.44 mmol) and DBU (0.64ml, 0 mol) in MeCN (20 ml) at room temperature for 16 h gave the crudeMichael intermediate (50%, 697 mg, 0.72 mmol) which was then reactedwith iron powder (40 mg) in AcOH (4 ml) at 80° C. for 1.5 h to give thetitle compound (99 mg, 32%) as a pale yellow solid after purification byflash column chromatography eluting 2-40% MeOH in DCM followed byprep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.57 (t, J=5.6 Hz, 1H), 8.38 (dt,J=4.3, 1.3 Hz, 1H), 7.73-7.66 (m, 1H), 7.45 (dd, J=5.7, 3.2 Hz, 2H),7.40 (dt, J=8.6, 4.4 Hz, 1H), 7.13-7.08 (m, 2H), 4.61 (d, J=5.5 Hz, 2H),3.06 (q, J=6.3 Hz, 4H), 2.97 (q, J=6.7 Hz, 4H), 2.60 (s, 3H)

HPLCMS (Method C): [m/z]: 439.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-5-methyl-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 188)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-5-methyl-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (114) (315 mg, 0.594 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (114 mg, 0.594 mmol) and DBU (0.266ml, 1.781 mmol) in MeCN (12 ml) at room temperature for 3 h gave therequired Michael intermediate (142 mg, 42%) as a yellow oil afterpurification using isolute silica column eluting with a gradient of 0-6%MeOH in DCM.

The Michael intermediate (142 mg, 0.248 mmol) was reacted with ironpowder (42 mg) in AcOH (3 ml) at 80° C. for 1.5 h to give the titlecompound (7 mg, 7%) as a brown solid after purification by basicprep-HPLC followed by isolute silica column chromatography eluting witha gradient of 0-8% MeOH in DCM.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.72 (d, J=4.9 Hz, 2H), 7.43 (dt,J=6.6, 3.3 Hz, 2H), 7.35 (t, J=4.9 Hz, 1H), 7.19 (dt, J=6.0, 3.4 Hz,2H), 4.65 (s, 2H), 3.24 (t, J=6.8 Hz, 2H), 3.22-3.17 (m, 4H), 3.15 (t,J=6.6 Hz, 2H), 2.68 (s, 3H)

HPLCMS (Method D): [m/z]: 422.2 [M+H]⁺

BenzylN-(3-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}propyl)carbamate(Example Compound No. 179)

In a similar fashion to general procedure 3,2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 94—freebase) (166 mg, 0.391 mmol), benzyl(3-oxopropyl)carbamate (97 mg, 0.469 mmol) and DIPEA (0.12 ml, 0.587mmol) in MeOH (1 ml) at room temperature for 1 h, followed by theaddition of NaBH₄ (22 mg, 0.587 mmol) afforded the title compound (94mg, 39%) as a pale yellow oil after purification by flash chromatography(eluting with a gradient of 0-5% MeOH/DCM).

HPLCMS (Method F): [m/z]: 616.2 [M+H]⁺

2-{2-[(3-Aminopropyl)[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 163)

A solution of benzylN-(3-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}propyl)carbamate(Example Compound No. 179) (45 mg, 0.073 mmol) in AcOH/HBr (1:1, 1 ml)was stirred at 50° C. for 2 h. The reaction mixture was evaporated invacuo. Purification by basic prep-HPLC afforded the title compound (16mg, 45%) as a colourless oil.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.32 (d, J=4.7 Hz, 1H), 7.90 (s,1H), 7.63-7.52 (m, 1H), 7.44 (dt, J=6.6, 3.3 Hz, 2H), 7.35 (dt, J=8.6,4.4 Hz, 1H), 7.17 (dt, J=6.0, 3.3 Hz, 2H), 4.75 (d, J=1.5 Hz, 2H), 3.20(t, J=6.6 Hz, 2H), 3.04 (s, 4H), 2.98 (t, J=6.6 Hz, 2H), 2.65 (m, 4H),1.67 (m, 2H)

HPLCMS (Method D): [m/z]: 482.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl](butyl)amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 157)

In a similar fashion to general procedure 3,2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 94—freebase) (60 mg, 0.141 mmol), butanal (12 mg,0.174 mmol) and DIPEA (98 μl, 0.56 mmol) in MeOH (1 ml) at roomtemperature for 1 h followed by the addition of NaBH₄ (8 mg, 0.21 mmol)afforded the title compound (50 mg, 73%) as a yellow oil afterpurification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.13 (s, 1H), 8.66 (t, J=5.6 Hz, 1H),8.37 (d, J=4.7 Hz, 1H), 8.06 (s, 1H), 7.69 (ddd, J=9.9, 8.4, 1.2 Hz,1H), 7.57-7.32 (m, 3H), 7.17-7.01 (m, 2H), 4.65 (d, J=4.6 Hz, 2H), 3.17(t, J=6.7 Hz, 2H), 2.96 (m, 4H), 2.88 (t, J=6.7 Hz, 2H), 2.58-2.51 (m,2H), 1.40 (m, 2H), 1.23 (m, 2H), 0.83 (t, J=7.4 Hz, 3H)

HPLCMS (Method D): [m/z]: 481.3 [M+H]⁺

2-(2-{bis[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 152)

In a similar fashion to general procedure 7,2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 94—freebase) (400 mg, 1.13 mmol),2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (492 mg, 2.27 mmol)and DIPEA (3.03 ml, 17 mol) in DMF (5 ml) at 30° C. for 3 d, affordedthe title compound (10 mg, 1.5%) as an off-white solid afterpurification by basic prep-HPLC followed by flash column chromatography(eluting with a gradient of 0-10% MeOH/DCM followed by 0-10% 7N ammoniain MeOH/DCM) and a second basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.28 (s, 1H), 8.66 (t, J=5.7 Hz, 1H),8.37 (dt, J=4.6, 1.4 Hz, 1H), 8.06 (s, 1H), 7.69 (ddd, J=10.0, 8.3, 1.3Hz, 1H), 7.61-7.46 (m, 3H), 7.39 (dq, J=8.6, 4.2 Hz, 2H), 7.23-7.04 (m,4H), 4.77-4.52 (m, 4H), 3.27 (t, J=7.2 Hz, 2H), 3.15-3.04 (m, 2H),3.02-2.90 (m, 4H), 2.87 (t, J=6.7 Hz, 2H)

HPLCMS (Method B): [m/z]: 569.3 [M+H]⁺

2-{2-[bis(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 166)

In a similar fashion to general procedure 7,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 40) (110 mg, 0.268 mmol),2-(chloromethyl)-1H-1,3-benzodiazole (45 mg, 0.268 mmol), DIPEA (0.467ml, 2.68 mmol) in DMF (1 ml) at 45° C. for 3 h then at 55° C. for 1 h,afforded the title compound (10 mg, 7%) as a white solid afterpurification by basic prep-HPLC followed by flash column chromatography(eluting with a gradient of 0-10% MeOH/DCM followed by 0-10% 7N ammoniain MeOH/DCM).

1H-NMR (Acetone-d6, 500 MHz): d[ppm]=11.99 (s, 1H), 8.43 (s, 1H), 8.33(d, J=4.7 Hz, 1H), 8.02 (s, 1H), 7.71-7.55 (m, 3H), 7.51 (s, 2H), 7.37(dt, J=8.5, 4.4 Hz, 1H), 7.17 (d, J=5.7 Hz, 4H), 4.80-4.70 (m, 2H), 4.17(s, 4H), 3.37 (t, J=6.9 Hz, 2H), 3.20 (t, J=6.9 Hz, 2H)

HPLCMS (Method B): [m/z]: 541.3 [M+H]⁺

2-(2-{[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 243)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (662 mg, 1.87 mmol),N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (394 mg, 1.87 mmol) and DBU(924 μl, 6.18 mmol) in MeCN (10 ml) gave a crude intermediate which wasfurther reacted with iron powder (286 mg, 5.12 mmol) in AcOH (15 ml) toafford the title compound (203 mg, 34%) as a white solid afterpurification by basic prep-HPLC followed by flash column chromatography(eluting with a gradient of 0-20% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.66 (t, J=5.6 Hz, 1H), 8.39 (dt,J=4.7, 1.3 Hz, 1H), 8.08 (s, 1H), 7.70 (ddd, J=10.0, 8.4, 1.1 Hz, 1H),7.40 (dt, J=8.7, 4.4 Hz, 1H), 7.27 (d, J=8.0 Hz, 1H), 7.10 (td, J=8.0,4.9 Hz, 1H), 6.92 (dd, J=11.1, 8.0 Hz, 1H), 4.68-4.62 (m, 2H), 3.16 (t,J=6.7 Hz, 2H), 3.05 (t, J=6.7 Hz, 2H), 2.99 (t, J=6.6 Hz, 4H)

HPLCMS (Method B): [m/z]: 443.2 [M+H]⁺

2-(2-{[(4-fluoro-1H-1,3-benzodiazol-2-yl)methyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 253)

In a similar fashion to general procedure 7,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (100 mg, 0.3 mmol),2-(chloromethyl)-7-fluoro-1H-1,3-benzodiazole hydrochloride (66 mg, 0.3mmol) and DIPEA (258 μl, 1.48 mmol) in DMF (2.5 ml) was stirred at 40°C. for 73 h, to afforded the title compound (23 mg, 18%) as a brownglassy solid after purification by reverse phase Biotage (A=water/0.1%NH₃; B=MeCN/0.1% NH₃; eluting with a gradient of 10% A/B for 2 columnvolumes, 10% to 30% A/B for 4 column volumes, 30% to 60% A/B for 10column volumes and 60% to 100% for 5 column volumes).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.49 (br s, 1H), 8.54-8.47 (m, 2H),8.39-8.34 (m, 1H), 7.73-7.65 (m, 1H), 7.42-7.37 (m, 1H), 7.34-7.24 (m,1H), 7.15-7.06 (m, 1H), 6.92 (t, 1H), 4.63-4.57 (m, 2H), 3.99-3.91 (m,2H), 3.02-2.94 (m, 4H), 2.63 (br s, 1H)

HPLCMS (Method D): [m/z]: 413.2 [M+H]⁺

2-(2-{[(4-fluoro-1H-1,3-benzodiazol-2-yl)methyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 274)

In a similar fashion to general procedure 7,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (200 mg, 0.57 mmol),2-(chloromethyl)-7-fluoro-1H-1,3-benzodiazole hydrochloride (125 mg,0.57 mmol) and DIPEA (493 μl, 2.83 mmol) in DMF (5.5 ml) was heated at40° C. for 18 h, stirred at room temperature for 2 d and then heated at40° C. for 4 h to give the title compound (7 mg, 3%) as a glassy brownsolid after purification by reverse phase chromatography [(eluting witha gradient of 10-100% (water+0.1% ammonia)/(MeCN+0.1% ammonia)].

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.50 (s, 1H), 8.70-8.61 (m, 1H),8.39-8.32 (m, 1H), 8.13 (s, 1H), 7.72-7.66 (m, 1H), 7.42-7.36 (m, 1H),7.34-7.25 (m, 1H), 7.15-7.08 (m, 1H), 6.93 (m, 1H), 4.68-4.62 (m, 2H),4.00-3.94 (m, 2H), 3.22-3.15 (m, 2H), 3.01-2.93 (m, 2H), 2.71 (s, 1H)

HPLCMS (Method D): [m/z]: 429.1 [M+H]⁺

General Scheme 6 Above General Procedure 9:2-{2-[(1H-1,3-Benzodiazol-2-yl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (Example Compound No. 121)

A solution of2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (1.65 g, 2.62 mmol, 56% purity),2-chloro-1H-benzimidazole (0.1 g, 0.66 mmol) and DIPEA (0.571 ml, 3.277mmol) in n-butanol (3 ml) and MeOH (0.1 ml) was heated at 150° C. undermicrowave irradiation for 2.5 h. The reaction mixture was concentratedin vacuo. The residue was dissolved in saturated NaHCO₃ solution,diluted with water (20 ml) and extracted with 4:1 chloroform/IPA (4×20ml). The combined organic extracts were dried (MgSO₄), filtered andevaporated in vacuo.

The residue was purified by flash column chromatography (kp-NH, elutingwith a gradient of 0-10% MeOH/EtOAc) followed by basic prep-HPLC. Theresidue obtained was dissolved in MeOH (4 ml) and treated with 12 M HCl(1 ml) for 2 h. Evaporation in vacuo afforded the title compound (0.131g, 43%) as a white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.60 (d, J=5.5 Hz, 1H), 8.31 (t,J=8.3 Hz, 1H), 8.19 (s, 1H), 7.93 (br, J=3.8 Hz, 1H), 7.38 (dt, J=7.1,3.5 Hz, 2H), 7.28 (dd, J=5.9, 3.2 Hz, 2H), 4.93 (s, 2H), 3.99 (t, J=6.4Hz, 2H), 3.49 (t, J=6.4 Hz, 2H)

HPLCMS (Method D): [m/z]: 397.1 [M+H]⁺

2-{3-[(1H-1,3-Benzodiazol-2-yl)amino]propyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 135)

In a similar fashion to general procedure 9,2-(3-aminopropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (115) (173 mg, 0.472 mmol), 2-chloro-1H-benzimidazole(60 mg, 0.393 mmol), DIPEA (0.21 ml, 1.18 mmol), n-BuOH (2 ml) and DMF(0.5 ml) at 150° C. in the microwave for 1 h, gave the title compound(26 mg, 16%) as an off-white solid after purification by basicprep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=10.74 (s, 1H), 8.68 (t, J=5.7 Hz, 1H),8.37 (dt, J=4.7, 1.4 Hz, 1H), 8.15 (s, 1H), 7.70 (ddd, J=10.0, 8.3, 1.3Hz, 1H), 7.40 (dt, J=8.6, 4.4 Hz, 1H), 7.11 (dd, J=14.8, 7.6 Hz, 2H),6.96-6.75 (m, 2H), 6.67 (t, J=5.7 Hz, 1H), 4.65 (dd, J=5.7, 1.4 Hz, 2H),3.39 (q, J=6.7 Hz, 2H), 3.18-3.07 (m, 2H), 2.07 (m, 2H)

HPLCMS (Method D): [m/z]: 411.2 [M+H]⁺

General Scheme 7 Above Ethyl2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}methyl)-1,3-thiazole-4-carboxylate(120)

In a similar fashion to general procedure 3,2-(1H-benzimidazol-2-yl)ethanamine dihydrochloride (379 mg, 1.62 mmol),ethyl 2-formyl-1,3-thiazole-4-carboxylate (300 mg, 1.62 mmol), DIPEA(1.13 ml, 6.48 mmol) and MgSO₄ (100 mg) in DCM (10 ml) at roomtemperature for 24 h, followed by addition of NaBH₄ (92 mg, 2.43 mmol)gave the title compound (201 mg, 35%) as a white solid afterpurification by flash column chromatography (kp-NH, eluting with agradient of 0-15% MeOH/EtOAc).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.40 (s, 1H), 7.51 (d,J=7.8 Hz, 1H), 7.40 (d, J=7.1 Hz, 1H), 7.16-7.07 (m, 2H), 4.28 (q, J=7.1Hz, 2H), 4.05 (m, 2H), 3.04 (m, 2H), 2.99 (t, J=5.8 Hz, 2H), 2.52 (s,2H), 1.29 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 331.0 [M+H]⁺

Ethyl2-({[3-(1H-1,3-benzodiazol-2-yl)propyl]amino}methyl)-1,3-thiazole-4-carboxylate(121)

In a similar fashion to general procedure 3,3-(1H-benzimidazol-2-yl)propan-1-amine (568 mg, 3.24 mmol), ethyl2-formyl-1,3-thiazole-4-carboxylate (600 mg, 3.24 mmol), DIPEA (2.26 ml,12.96 mmol) and MgSO₄ (300 mg) in DCM (20 ml) at room temperature for 24h, followed by addition of NaBH₄ (184 mg, 4.86 mmol) afforded the titlecompound (570 mg, 31%, 62% purity) as a white solid after purificationby flash column chromatography (kp-NH, eluting with a gradient of 0-10%MeOH/EtOAc).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.39 (s, 1H), 7.50 (d,J=6.9 Hz, 1H), 7.39 (d, J=7.0 Hz, 1H), 7.14-7.05 (m, 2H), 4.28 (q, J=7.1Hz, 2H), 3.99 (m, 2H), 2.87 (t, J=7.6 Hz, 2H), 1.94 (q, J=7.3 Hz, 2H),1.29 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 345.00 [M+H]⁺

Tert-butyl2-(2-{[(tert-butoxy)carbonyl]({[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]methyl})amino}ethyl)-1H-1,3-benzodiazole-1-carboxylate(122)

In a similar fashion to general procedure 4, ethyl2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}methyl)-1,3-thiazole-4-carboxylate(120) (201 mg, 0.608 mmol), Boc₂O (146 mg, 0.669 mmol) and TEA (0.08 ml,0.608 mmol) in THF (10 ml) at room temperature for 20 h, gave theafforded the title compound (345 mg, 94%) as a colourless oil afterpurification by flash column chromatography (eluting with a gradient of40-100% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 531.15 [M+H]⁺

Tert-butyl2-(3-{[(tert-butoxy)carbonyl]({[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]methyl})amino}propyl)-1H-1,3-benzodiazole-1-carboxylate(123)

In a similar fashion to general procedure 4, ethyl2-({[3-(1H-1,3-benzodiazol-2-yl)propyl]amino}methyl)-1,3-thiazole-4-carboxylate(121) (0.570 g, 1.018 mmol, 62% purity), Boc₂O (1.56 g, 7.124 mmol) andTEA (0.671 ml, 5.089 mmol) in THF (40 ml) at room temperature for 72 h,following further Boc₂O (0.444 g, 2.036 mmol) for 4 h and furtheraddition of Boc₂O (0.444 g, 2.036 mmol) for more 16 h, gave the titlecompound (1.162 g, 48% purity, quant.) as a yellow oil afterpurification by flash column chromatography (eluting with a gradient of0-60% EtOAc/heptane).

HPLCMS (Method A): [m/z]: 545.15 [M+H]⁺

2-({[2-(1H-1,3-Benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}methyl)-1,3-thiazole-4-carboxylicacid (124)

In a similar fashion to general procedure 5, tert-butyl2-(2-{[(tert-butoxy)carbonyl]({[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]methyl})amino}ethyl)-1H-1,3-benzodiazole-1-carboxylate(122) (385 mg, 0.73 mmol) and LiOH (87 mg, 3.63 mmol) in THF/water (25ml/5 ml) afforded the title compound (350 mg, 99%, 83% purity) as awhite solid.

HPLCMS (Method A): [m/z]: 403.00 [M+H]⁺

2-({[3-(1H-1,3-Benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}methyl)-1,3-thiazole-4-carboxylicacid (125)

In a similar fashion to general procedure 5, tert-butyl2-(3-{[(tert-butoxy)carbonyl]({[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]methyl})amino}propyl)-1H-1,3-benzodiazole-1-carboxylate(123) (1.16 g, 1.02 mmol, 48% purity) and LiOH (122 mg, 5.09 mmol) inTHF/water (20 ml/5 ml) afforded the crude title compound (811 mg, 52%purity) as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.39 (s, 1H), 7.65 (br s, 2H), 7.37(br s, 2H), 4.68 (br s, 2H), 3.38 (br s, 2H), 3.00 (br s, 2H), 2.08 (brs, 2H), 1.34 (s, 9H)

HPLCMS (Method A): [m/z]: 417.05 [M+H]⁺

Tert-butylN-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)methyl]carbamate(126)

In a similar fashion to general procedure 6,2-({[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}methyl)-1,3-thiazole-4-carboxylicacid (124) (175 mg, 0.36 mmol, 83% purity),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (108 mg, 0.54mmol), DIPEA (0.25 ml, 1.44 mmol) and HATU (206 mg, 0.54 mmol) in DMF (4ml) afforded the title compound (81 mg, 44%) as a colourless solid afterpurification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.24 (s, 1H), 8.75 (s, 1H), 8.36 (s,1H), 8.22 (s, 1H), 7.73-7.66 (m, 1H), 7.50 (s, 1H), 7.46-7.37 (m, 2H),7.11 (s, 2H), 4.72 (s, 2H), 4.66 (d, J=4.4 Hz, 2H), 3.76 (m, 2H),3.20-3.05 (m, 2H), 1.30 (s, 9H)

HPLCMS (Method A): [m/z]: 511.10 [M+H]⁺

Tert-butylN-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)methyl]carbamate(127)

In a similar fashion to general procedure 6,2-({[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}methyl)-1,3-thiazole-4-carboxylicacid (125) (406 mg, 0.51 mmol, 52% purity),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (152 mg, 0.76mmol), DIPEA (0.36 ml, 2.04 mmol) and HATU (291 mg, 0.76 mmol) in DMF (4ml) afforded the title compound (215 mg, 75%) as a white solid afterpurification by flash column chromatography (kp-NH, eluting with agradient of 70-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.68 (t, J=5.5 Hz, 1H),8.36 (s, 1H), 8.22 (s, 1H), 7.69 (t, J=9.3 Hz, 1H), 7.52-7.45 (m, 1H),7.42-7.34 (m, 2H), 7.09 (s, 2H), 4.71 (s, 2H), 4.65 (d, J=5.5 Hz, 2H),3.41 (s, 2H), 2.81 (t, J=7.3 Hz, 2H), 2.04 (m, 2H), 1.34 (s, 9H)

HPLCMS (Method A): [m/z]: 525.15 [M+H]⁺

Tert-butylN-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-y)methyl]carbamate(128)

In a similar fashion to general procedure 6,2-({[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}methyl)-1,3-thiazole-4-carboxylicacid (125) (0.146 g, 0.351 mmol), (3,5-difluoropyridin-2-yl)methanaminedihydrochloride (0.114 g, 0.526 mmol), DIPEA (0.305 ml, 1.753 mmol) andHATU (0.227 g, 0.526 mmol) in DMF (3 ml) at room temperature for 2 hafforded the title compound (0.071 g, 37%) as a glassy solid afterpurification by basic prep-HPLC.

¹H NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.73-8.66 (m, 1H),8.47-8.41 (m, 1H), 8.24-8.18 (m, 1H), 7.95-7.87 (m, 1H), 7.52-7.45 (m,1H), 7.41-7.35 (m, 1H), 7.15-7.05 (m, 2H), 4.70 (s, 2H), 4.61 (d, J=5.7Hz, 2H), 3.45-3.38 (m, 2H), 2.85-2.77 (m, 2H), 2.07-1.99 (m, 2H), 1.34(s, 9H)

HPLCMS (Method A): [m/z]: 543.15 [M+H]⁺

2-({[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 118)

In a similar fashion to general procedure 2, tert-butylN-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)methyl]carbamate(126) (81 mg, 0.159 mmol) and 12M HCl (0.53 ml) in MeOH (5 ml) at roomtemperature for 4 d and then at 40° C. for 4 h afforded the titlecompound (49 mg, 58%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.81 (s, 1H), 8.41 (s, 1H), 8.36 (dt,J=4.7, 1.4 Hz, 1H), 7.78 (dd, J=6.1, 3.1 Hz, 2H), 7.72 (ddd, J=10.0,8.4, 1.2 Hz, 1H), 7.53 (dd, J=6.0, 3.1 Hz, 2H), 7.40 (dd, J=8.4, 4.3 Hz,1H), 4.73 (s, 2H), 4.69 (d, J=5.1 Hz, 2H), 3.79 (br s, 2H), 3.73 (br s,2H)

HPLCMS (Method D): [m/z]: 411.1 [M+H]⁺

2-({[3-(1H-1,3-Benzodiazol-2-yl)propyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 119)

In a similar fashion to general procedure 2, 12M HCl (0.635 ml) wasadded to a solution of tert-butylN-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)methyl]carbamate(127) (215 mg, 0.381 mmol) in MeOH (5 ml) and the mixture stirred for 16h.

Further 12M HCl (0.635 ml, 7.623 mmol) was added and the mixture stirredfor a further 20 h. The reaction mixture was evaporated in vacuo toafford the title compound (139 mg, 68%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.96 (br s, 1H), 8.78 (br s, 1H), 8.40(s, 1H), 8.38 (d, J=4.4 Hz, 1H), 7.80-7.76 (m, 2H), 7.73 (t, J=8.1 Hz,1H), 7.55-7.51 (m, 2H), 7.44-7.39 (m, 1H), 4.70 (d, J=4.6 Hz, 2H), 4.64(s, 2H), 3.35 (t, J=7.2 Hz, 2H), 3.23 (t, J=7.4 Hz, 2H), 2.39-2.33 (m,2H)

HPLCMS (Method D): [m/z]: 425.2 [M+H]⁺

2-({[3-(1H-1,3-Benzodiazol-2-yl)propyl]amino}methyl)-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (Example Compound No. 124)

In a similar fashion to general procedure 2, 12M HCl (0.524 ml, 6.28mmol) was added to a solution tert-butyl tert-butylN-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)methyl]carbamate(128) (0.071 g, 0.131 mmol) in MeOH (3 ml) at 45° C. for 4 h, to givethe title compound (0.036 g, 53%) as a white solid.

¹H NMR (Methanol-d4, 500 MHz): d[ppm]=8.37 (s, 1H), 8.35-8.30 (m, 1H),7.81-7.76 (m, 2H), 7.66-7.57 (m, 3H), 4.79 (s, 2H), 4.74 (s, 2H),3.45-3.36 (m, 4H), 2.51-2.41 (m, 2H)

HPLCMS (Method D): [m/z]: 443.2 [M+H]⁺

General Scheme 8 Above General Procedure 10:3-Bromo-N-(2-nitrophenyl)propanamide (129)

3-Bromopropanoyl chloride (1.59 ml, 15.75 mmol) was added dropwise to anice-cold solution of 2-nitroaniline (2.18 g, 15.75 mmol) and TEA (2.63ml, 18.9 mmol) in toluene (50 ml) and the mixture stirred for 2 h. Thereaction mixture was concentrated in vacuo and the residue trituratedwith water (10 ml) to give a brown precipitate which was collected byfiltration. Purification by flash column chromatography (eluting with agradient of 0-10% EtOAc/heptane) afforded the title compound (0.988 g,23%) as a yellow crystalline solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=10.45 (s, 1H), 8.81 (dd, J=8.5, 1.2 Hz,1H), 8.25 (dd, J=8.5, 1.6 Hz, 1H), 7.78-7.61 (m, 1H), 7.24 (ddd, J=8.5,7.3, 1.3 Hz, 1H), 3.74 (t, J=6.5 Hz, 2H), 3.11 (t, J=6.5 Hz, 2H)

HPLCMS (Method A): [m/z]: 272.95/274.90 [M+H]⁺

3-Bromo-N-(4-fluoro-2-nitrophenyl)propanamide (130)

In a similar fashion to general procedure 10, 3-bromopropanoyl chloride(2.29 ml, 23.06 mmol), 4-fluoro-2-nitroaniline (3 g, 19.22 mmol) and TEA(3.124 ml, 23.06 mmol) in toluene (35 ml) at room temperature for 40 hafforded the title compound (3.04 g, 42%) as a yellow solid afterpurification by flash column chromatography (eluting with a gradient of0-40% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=10.38 (s, 1H), 7.91 (dd, J=8.6, 2.5Hz, 1H), 7.65-7.60 (m, 2H), 3.68 (t, J=6.4 Hz, 2H), 2.97 (t, J=6.4 Hz,2H)

HPLCMS (Method A): [m/z]: 290.75/292.75 [M+H]⁺

4-Bromo-N-(2-nitrophenyl)butanamide (131)

In a similar fashion to general procedure 10, 4-bromobutanoyl chloride(1.56 ml, 13.48 mmol), 2-nitroaniline (1.55 g, 11.24 mmol) and TEA(1.566 ml, 11.2 mmol) in toluene (25 ml) at room temperature for 16 h,gave the title compound (2.35 g, 41%) as a yellow oil after purificationby flash column chromatography (eluting with a gradient of 0-40%EtOAc/heptane).

¹H NMR (DMSO-d6, 500 MHz): d[ppm]=10.33 (s, 1H), 7.93 (dd, J=8.2, 1.4Hz, 1H), 7.72-7.65 (m, 1H), 7.58 (dd, J=8.1, 1.2 Hz, 1H), 7.38-7.34 (m,1H), 3.58 (t, J=6.6 Hz, 2H), 2.51 (t, J=6.6 Hz, 2H, obscured by DMSO),2.13-2.06 (m, 2H)

HPLCMS (Method A): [m/z]: 288.75 [M+H]⁺

General Procedure 11: Ethyl2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxylate(132)

To a solution of 3-Bromo-N-(2-nitrophenyl)propanamide (129) (1.04 g, 3.8mmol) in DMF (10 ml) was added dropwise over 20 min to a mixture ofethyl 2-(2-aminoethyl)-1,3-thiazole-4-carboxylate hydrochloride (1 g,3.8 mmol, 90% purity) and Na₂CO₃ (0.48 g, 4.56 mmol) in DMF (30 ml). Thereaction mixture was stirred for 16 h at room temperature. Water (10 ml)was added and the mixture extracted with EtOAc (3×20 ml). The combinedorganic extracts were washed with brine (10 ml), dried (MgSO₄), filteredand evaporated in vacuo to give the crude title compound (1.5 g, 70%,70% purity) which was used without purification.

HPLCMS (Method A): [m/z]: 393.1 [M+H]⁺

Ethyl2-[2-({2-[(4-fluoro-2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxylate(133)

In a similar fashion to general procedure 11,3-bromo-N-(4-fluoro-2-nitrophenyl)propanamide (130) (1 g, 2.68 mmol),ethyl 2-(2-aminoethyl)-1,3-thiazole-4-carboxylate hydrochloride (0.634g, 2.68 mmol) and Na₂CO₃ (0.426 g, 4.02 mmol) in DMF (10 ml) at roomtemperature for 24 h gave the crude title compound (2.26 g, 80%, 39%purity) which was used without purification.

HPLCMS (Method A): [m/z]: 411 [M+H]⁺

Ethyl2-[2-({3-[(2-nitrophenyl)carbamoyl]propyl}amino)ethyl]-1,3-thiazole-4-carboxylate(134)

In a similar fashion to general procedure 11,4-Bromo-N-(2-nitrophenyl)butanamide (131) (2.35 g, 4.65 mmol), ethyl2-(2-aminoethyl)-1,3-thiazole-4-carboxylate hydrochloride (1.10 g, 4.66mmol), Na₂CO₃ (0.74 g, 6.98 mmol) and DMF (25 ml) at room temperaturefor 16 h gave the crude title compound (3.0 g, quant.) as yellow oil,which was used in the next step without purification.

HPLCMS (Method A): [m/z]: 407 [M+H]⁺

Ethyl2-(2-{[(tert-butoxy)carbonyl]({2-[(2-nitrophenyl)carbamoyl]ethyl})amino}ethyl)-1,3-thiazole-4-carboxylate(135)

In a similar fashion to general procedure 4, ethyl2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxylate(132) (1.3 g, 1.99 mmol, 60% purity), Boc₂O (477 mg, 2.19 mmol) and TEA(413 μl, 2.9 mmol) in THF (50 ml) were stirred at room temperature for16 h. Additional Boc₂O (477 mg, 2.19 mmol) and TEA (413 μl, 2.98 mmol)were added and the mixture was stirred for a further 4 h. The reactionmixture was evaporated in vacuo, the residue was dissolved in EtOAc (10ml) and washed with water (3×5 ml). The organic layer was dried (MgSO₄),filtered and evaporated in vacuo.

Purification by flash column chromatography (eluting with a gradient of10-100% EtOAc/heptane) afforded the title compound (132 mg, 12%) as ayellow oil.

HPLCMS (Method A): [m/z]: 493.15 [M+H]⁺

Ethyl2-(2-{[(tert-butoxy)carbonyl]({2-[(4-fluoro-2-nitrophenyl)carbamoyl]ethyl})amino}ethyl)-1,3-thiazole-4-carboxylate(136)

In a similar fashion to general procedure 4,2-[2-({2-[(4-fluoro-2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxylate(133) (2.26 g, 2.145 mmol), Boc₂O (1.87 g, 8.58 mmol) and TEA (0.848 ml,6.43 mmol) in THF (60 ml at room temperature for 16 h gave the titlecompound (0.43 g, 38%) as a yellow oil after purification by flashcolumn chromatography (eluting with a gradient of 10-100%EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=10.30 (s, 1H), 8.41 (s, 1H), 7.89 (d,J=8.5 Hz, 1H), 7.62 (m, 2H), 4.29 (q, J=7.1 Hz, 2H), 3.54 (m, 2H), 3.41(t, J=7.1 Hz, 2H), 3.22 (t, J=7.0 Hz, 2H), 2.58 (m 2H), 1.35-1.27 (m,12H)

HPLCMS (Method A): [m/z]: 511.1 [M+H]⁺

Ethyl2-(2-{[(tert-butoxy)carbonyl]({3-[(2-nitrophenyl)carbamoyl]propyl})amino}ethyl)-1,3-thiazole-4-carboxylate(137)

In a similar fashion to general procedure 4, ethyl2-[2-({3-[(2-nitrophenyl)carbamoyl]propyl}amino)ethyl]-1,3-thiazole-4-carboxylate(134) (3.0 g, 5.32 mmol, 72% purity), Boc₂O (2.44 g, 11.17 mmol) and TEA(2.10 ml, 15.96 mmol) in THF (50 ml) were stirred at room temperaturefor 24 h. additional Boc₂O (2.32 g, 10.64 mmol) and TEA (0.7 ml, 5.32mmol) were added and the reaction stirred at room temperature for 96 h,to give the title compound (0.287 g, 10%) as a yellow oil afterpurification by reverse-phase column chromatography (eluting with agradient of 0-100% MeCN/water) gave

¹H NMR (DMSO-d6, 500 MHz): d[ppm]=10.23 (s, 1H), 8.40 (s, 1H), 7.93 (dd,J=8.2, 1.4 Hz, 1H), 7.71-7.66 (m, 1H), 7.62 (dd, J=8.1, 1.4 Hz, 1H),7.37-7.32 (m, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.53 (t, J=6.9 Hz, 2H),3.25-3.15 (m, 4H), 2.32 (t, J=7.4 Hz, 2H), 1.81-1.72 (m, 2H), 1.40-1.29(br m, 9H), 1.28 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 507.1 [M+H]⁺

Ethyl2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate(138)

A suspension of ethyl2-(2-{[(tert-butoxy)carbonyl]({2-[(2-nitrophenyl)carbamoyl]ethyl})amino}ethyl)-1,3-thiazole-4-carboxylate(135) (175 mg, 0.36 mmol) and iron powder (238 mg, 4.26 mmol) in AcOHwas heated at 80° C. for 1 h. The reaction mixture was cooled to roomtemperature, diluted with DCM (10 ml) and neutralised with sat. NaHCO₃.The aqueous phase was extracted with DCM (3×10 ml), dried (Na₂SO₄),filtered and evaporated in vacuo to afford the title compound (121 mg,76%) as a pale yellow oil.

HPLCMS (Method A): [m/z]: 445.15 [M+H]⁺

Ethyl2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-thiazole-4-carboxylate(139)

A suspension of ethyl2-(2-{[(tert-butoxy)carbonyl]({2-[(4-fluoro-2-nitrophenyl)carbamoyl]ethyl})amino}ethyl)-1,3-thiazole-4-carboxylate(136) (0.43 g, 0.825 mmol) and iron powder (0.533 g, 9.905 mmol) in AcOH(40 ml) was heated at 80° C. for 2 h. The reaction mixture was cooled toroom temperature and neutralised by slow addition sat. Na₂CO₃. Themixture was extracted with DCM (4×40 ml) and the combined organicextracts were dried (MgSO₄), filtered and evaporated in vacuo to affordthe title compound as an off-white glassy solid (0.445 g, quant).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.34 (s, 1H), 8.40 (s, 1H), 7.27 (s,2H), 6.96 (s, 1H), 4.28 (q, J=7.1 Hz, 2H), 3.59 (t, J=7.1 Hz, 2H), 3.55(br s, 2H), 3.22 (br s, 2H), 3.00 (br s, 2H), 1.34-1.20 (m, 12H)

HPLCMS (Method A): [m/z]: 463.1 [M+H]⁺

Ethyl2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate(140)

Iron powder (0.368 g, 6.595 mmol) was added to ethyl2-(2-{[(tert-butoxy)carbonyl]({3-[(2-nitrophenyl)carbamoyl]propyl})amino}ethyl)-1,3-thiazole-4-carboxylate(137) (0.287 g, 0.55 mmol, 97% purity) in AcOH (10 ml). The reaction wasstirred at 80° C. for 1 h. The reaction was allowed to cool to roomtemperature. Water (50 ml) was added followed by Na₂CO₃ until pH 9. Theaqueous layer was extracted with DCM (4×50 ml). The combined organiclayers were dried (MgSO₄), filtered and the solvent evaporated to givethe title compound (0.291 g, quant) as a pale orange oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.39 (s, 1H), 7.53-7.47(m, 1H), 7.43-7.35 (m, 1H), 7.14-7.06 (m, 2H), 4.28 (q, J=7.1 Hz, 2H),3.58-3.51 (m, 2H), 3.26-3.21 (m, 4H), 2.77 (t, J=7.6 Hz, 2H), 2.01-1.91(m, 2H), 1.30 (s, 9H), 1.28 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 459.1 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylicacid (141)

In a similar fashion to general procedure 5, ethyl2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate(138) (156 mg, 0.35 mmol) and LiOH (33 mg, 1.35 mmol) in THF/water (5ml/1 ml) gave the title compound (100 mg, 68%) as a tan solid afteracidification with AcOH, extraction with 3:1 THF/EtOAc (3×10 ml), drying(MgSO₄), filtration and evaporation in vacuo.

HPLCMS (Method A): [m/z]: 417.1 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-thiazole-4-carboxylicacid (142)

In a similar fashion to general procedure 5, ethyl2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-thiazole-4-carboxylate(139) (380 mg, 0.83 mmol) and LiOH (59 mg, 2.48 mmol) in THF/water (45ml/15 ml) afforded the title compound (319 mg, 82%, 92% purity) as awhite solid.

HPLCMS (Method A): [m/z]: 435.05 [M+H]⁺

2-(2-{[3-(1H-1,3-Benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylicacid (143)

In a similar fashion to general procedure 5, ethyl2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate(140) (291 mg, 0.550 mmol, 87% purity) and LiOH (39 mg, 1.649 mmol) inTHF/water (25 ml/10 ml) at room temperature for 24 h, gave the titlecompound (219 mg, 72%) as a glassy solid.

1H-NMR (Acetone-d₆, 500 MHz): d[ppm]=7.87 (s, 1H), 7.06-6.96 (m, 2H),6.70-6.63 (m, 2H), 3.90-3.85 (m, 2H), 3.10 (t, J=6.8 Hz, 2H), 2.76 (t,J=7.0 Hz, 2H), 2.34 (t, J=7.4 Hz, 2H), 1.57-1.49 (m, 2H), 0.85 (s, 9H)

HPLCMS (Method A): [m/z]: 431.1 [M+H]⁺

Tert-butylN-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(144)

In a similar manner to general procedure 6,2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylicacid (141) (100 mg, 0.24 mmol), (3,5-difluoropyridin-2-yl)methanaminedihydrochloride (78 mg, 0.36 mmol), DIPEA (0.21 ml, 1.2 mmol) and HATU(137 mg, 0.36 mmol) in DMF (3 ml) afforded the title compound (77 mg,59%) as a white solid after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.30 (br s, 1H), 8.09 (s, 1H),7.55 (br s, 1H), 7.48 (s, 2H), 7.20 (d, J=3.3 Hz, 2H), 4.82 (s, 2H),4.73 (s, 2H), 3.70 (m, 4H), 3.08 (m, 2H), 1.16 (s, 9H)

HPLCMS (Method A): [m/z]: 543.15 [M+H]⁺

Tert-butylN-[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(145)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-thiazole-4-carboxylicacid (142) (160 mg, 0.34 mmol, 92% purity),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (101 mg, 0.51mmol), DIPEA (0.18 ml, 1.01 mmol) and HATU (192 mg, 0.51 mmol) in DMF (4ml) afforded the title compound (112 mg, 61%) as a white solid afterpurification by flash column chromatography (eluting with a gradient of0-50% MeOH/EtOAc).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.33 (br s, 1H), 8.66 (br s, 1H),8.36 (br s, 1H), 8.17 (br s, 1H), 7.72-7.66 (m, 1H), 7.53-7.36 (m, 2H),7.33-7.21 (m, 1H), 7.00-6.91 (m, 1H), 4.66 (d, J=4.5 Hz, 2H), 3.63 (t,J=7.0 Hz, 2H), 3.58 (t, J=6.9 Hz, 2H), 3.24 (t, J=6.9 Hz, 2H), 3.02 (m,2H), 1.35-1.18 (m, 9H)

HPLCMS (Method A): [m/z]: 543.1 [M+H]⁺

Tert-butylN-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]-N-[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate(146)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl][2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-thiazole-4-carboxylicacid (142) (12 mg, 0.28 mmol), (3,5-difluoropyridin-2-yl)methanaminedihydrochloride (90 mg, 0.41 mmol), DIPEA (0.24 ml, 1.38 mmol) and HATU(158 mg, 0.41 mmol) in DMF (3 ml) afforded the title compound (72 mg,47%) as a colourless glassy solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.33 (br s, 1H), 8.68 (br s, 1H),8.44 (br s, 1H), 8.16 (br s, 1H), 7.90 (d, J=11.0 Hz, 1H), 7.27 (br s,2H), 6.96 (br s, 1H), 4.62 (d, J=5.7 Hz, 2H), 3.65-3.57 (m, 4H), 3.22(m, 2H), 3.01 (br s, 2H), 1.24 (m, 9H)

HPLCMS (Method A): [m/z]: 561.15 [M+H]⁺

Tert-butylN-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(147)

In a similar fashion to general procedure 6,2-(2-{[3-(1H-1,3-benzodiazol-2-yl)propyl][(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylicacid (143) (219 mg, 0.39 mmol, 78% purity),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (118 mg, 0.59mmol), DIPEA (0.346 ml, 1.98 mmol) and HATU (226 mg, 0.59 mmol) in DMF(3 ml) at room temperature for 2 h gave the title compound (111 mg, 52%)as a colourless oil after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.66 (br s, 1H), 8.36(d, J=4.3 Hz, 1H), 8.16 (s, 1H), 7.73-7.63 (m, 1H), 7.52-7.45 (m, 1H),7.45-7.34 (m, 2H), 7.18-7.01 (m, 2H), 4.65 (d, J=5.5 Hz, 2H), 3.59 (t,J=7.0 Hz, 2H), 3.29-3.23 (m, 4H), 2.78 (t, J=7.5 Hz, 2H), 2.05-1.92 (m,2H), 1.30 (s, 9H)

HPLCMS (Method A): [m/z]: 539.15 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3,5-difluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 116)

In a similar fashion to general procedure 2, 12M HCl (0.378 ml, 4.541mmol) and tert-butylN-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-N-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (144) (77 mg, 0.142mmol) in MeOH (3 ml) at room temperature for 5 h and at 40° C. for 20 hgave the title compound (60 mg, 73%) as a yellow solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.29 (d, J=2.3 Hz, 1H), 8.23 (s,1H), 7.79 (dd, J=6.1, 3.2 Hz, 2H), 7.64-7.59 (m, 3H), 4.77 (s, 2H), 3.78(s, 4H), 3.72 (t, J=6.4 Hz, 2H), 3.59 (d, J=5.9 Hz, 2H)

HPLCMS (Method D): [m/z]: 443.1 [M+H]⁺

2-(2-{[2-(5-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 120)

In a similar fashion to general procedure 2, 12 M HCl (0.344 ml, 4.128mmol) andN-[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate (145) (112mg, 0.206 mmol) in MeOH (4 ml) at room temperature for 16 h, followingthe addition of 12M HCl (0.344 ml, 4.128 mmol) at room temperature forfurther 20 h and at 40° C. for 3 h, gave the title compound (80 mg, 67%)as a white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.57 (d, J=5.4 Hz, 1H), 8.28 (t,J=8.8 Hz, 1H), 8.25 (s, 1H), 7.89 (dt, J=9.5, 5.0 Hz, 1H), 7.81 (dd,J=9.0, 4.3 Hz, 1H), 7.58 (dd, J=8.1, 2.3 Hz, 1H), 7.42 (td, J=9.3, 2.4Hz, 1H), 4.97 (s, 2H), 3.85-3.79 (m, 4H), 3.75 (t, J=6.3 Hz, 2H), 3.62(t, J=6.3 Hz, 2H)

HPLCMS (Method D): [m/z]: 443.2 [M+H]⁺

N-[(3,5-Difluoropyridin-2-yl)methyl]-2-(2-{[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 123)

In a similar fashion to general procedure 2, 12 M HCl (0.257 ml, 3.08mmol) and tert-butylN-[2-(4-{[(3,5-difluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]-N-[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]carbamate(146) (72 mg, 0.128 mmol) in MeOH (3 ml) at room temperature for 16 h,following additional 12M HCl (0.257 ml, 3.08 mmol) and the mixturestirred at 45° C. for 4 h, gave the title compound (28 mg, 38%) as awhite solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.28 (d, J=2.3 Hz, 1H), 8.23 (s,1H), 7.79 (dd, J=9.0, 4.3 Hz, 1H), 7.60 (m, 1H), 7.56 (dd, J=8.1, 2.3Hz, 1H), 7.40 (td, J=9.3, 2.4 Hz, 1H), 4.76 (s, 2H), 3.77 (m, 4H), 3.73(t, J=6.4 Hz, 2H), 3.60 (t, J=6.4 Hz, 2H)

HPLCMS (Method D): [m/z]: 461.2 [M+H]⁺

2-(2-{[3-(1H-1,3-Benzodiazol-2-yl)propyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 125)

In a similar fashion to general procedure 2, 12M HCl (0.405 ml, 4.864mmol) and tert-butylN-[3-(1H-1,3-benzodiazol-2-yl)propyl]-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(147) (131 mg, 0.243 mmol) in MeOH (3 ml) at 40° C. for 16 h, gave thetitle compound (48 mg, 35%) as a white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.48 (d, J=5.1 Hz, 1H), 8.23 (s,1H), 8.07-8.00 (m, 1H), 7.80-7.76 (m, 2H), 7.74-7.66 (m, 1H), 7.63-7.58(m, 2H), 4.91 (s, 2H), 3.65 (t, J=6.4 Hz, 2H), 3.57 (t, J=6.6 Hz, 2H),3.41-3.32 (m, 4H), 2.49-2.40 (m, 2H)

HPLCMS (Method D): [m/z]: 439.2 [M+H]⁺

General Procedure 11: Tert-butyl3-carbamothioylpyrrolidine-1-carboxylate (148)

Lawesson reagent (0.42 g, 1.03 mmol) was added in one portion totert-butyl 3-carbamoylpyrrolidine-1-carboxylate (0.4 g, 1.87 mmol) inDCM (5 ml) and the reaction was stirred at room temperature for 2 h. Thereaction mixture was directly loaded onto silica and purified by flashcolumn chromatography (eluting with a gradient of 0-100% EtOAc/heptane)to give the title compound (0.36 g, 79%) as an off-white solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=7.46 (d, J=8.6 Hz, 1H), 7.01 (br s, 1H),3.75-3.66 (m, 1H), 3.65-3.54 (m, 1H), 3.59 (dd, 11 and 8.1 Hz, 1H), 3.37(q, J=8.7 Hz, 1H), 3.27 (p, J=7.8 Hz, 1H), 2.24-2.12 (m, 3H), 1.46 (s,9H)

HPLCMS (Method A): [m/z]: 252.95 [M+Na]⁺

Ethyl2-{1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazole-4-carboxylate(149)

In a similar fashion to general procedure 1, ethyl3-bromo-2-oxopropanoate (2.5 ml, 19.75 mmol), tert-butyl3-carbamothioylpyrrolidine-1-carboxylate (148) (3.96 g, 17.19 mmol) andCaCO₃ (0.87 g, 8.73 mmol) in EtOH (50 ml) at room temperature for 21 h,gave the title compound (2.84 g, 51.9%) as a yellow oil which solidifiedon standing, after purification by flash column chromatography (elutingwith a gradient of 0-70% EtOAc/heptane).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.08 (s, 1H), 4.41 (q, J=7.1 Hz, 2H),3.96-3.76 (m, 2H), 3.73-3.51 (m, 2H), 3.51-3.35 (m, 1H), 2.35-2.44 (m,1H), 2.28-2.14 (m, 1H), 1.46 (s, 9H), 1.39 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 349.05 [M+Na]⁺

2-{1-[(Tert-butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazole-4-carboxylicacid (150)

In a similar fashion to general procedure 5, LiOH (1.04 g, 43.5 mmol)and ethyl2-{1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazole-4-carboxylate(149) (2.84 g, 8.7 mmol) in THF (30 ml)/water (30 ml) gave the titlecompound (2.48 g, 93.6%) as a yellow solid. Compound was used in thenext step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=12.94 (s, 1H), 8.37 (s, 1H), 3.94-3.78(m, 1H), 3.78-3.68 (m, 1H), 3.49-3.39 (m, 2H), 2.44-2.24 (m, 1H),2.19-1.98 (m, 1H), 1.41 (s, 9H). A CH signal was obscured by the H₂Opeak

HPLCMS (Method A): [m/z]: 321.05 [M+Na]⁺ and 297.1 [M+H]⁺

Tert-butyl3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)pyrrolidine-1-carboxylate(151)

In a similar fashion using general procedure 6,2-{1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazole-4-carboxylicacid (150) (1 g, 3.35 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (1 g, 5.03 mmol), DIPEA (1.93 ml, 11.06 mmol), HATU(1.9 g, 5.03 mmol) in DMF (14 ml) gave the title compound (1.27 g, 86%)as a yellow oil after purification by flash column chromatography(eluting with a gradient of 0-100% EtOAc/heptane) followed byre-purification by flash column chromatography (eluting with a gradientof 0-10% MeOH/DCM).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.71 (t, J=5.6 Hz, 1H), 8.38 (dt,J=4.7, 1.4 Hz, 1H), 8.20 (s, 1H), 7.70 (ddd, J=10.2, 8.3, 1.3 Hz, 1H),7.40 (dt, J=8.5, 4.4 Hz, 1H), 4.66 (dd, J=5.7, 1.5 Hz, 2H), 3.94-3.81(m, 1H), 3.82-3.66 (m, 1H), 3.58-3.40 (m, 2H), 2.43-2.26 (m, 1H),2.25-2.04 (m, 1H), 1.40 (s, 9H). A CH signal was obscured by the H₂Opeak

HPLCMS (Method A): [m/z]: 407.1 [M+H]⁺

Tert-butyl3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}pyrrolidine-1-carboxylate(152)

In a similar fashion using general procedure 6,2-{1-[(tert-butoxy)carbonyl]pyrrolidin-3-yl}-1,3-thiazole-4-carboxylicacid (150) (1 g, 3.35 mmol), pyridin-2-ylmethanamine (0.52 ml, 5.03mmol), DIPEA (1.17 ml, 6.7 mmol) and HATU (1.9 g, 5.03 mmol) in DMF (14ml) gave the title compound (1.54 g, 100%) as a yellow solid afterpurification by flash column chromatography (eluting with a gradient of0-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.90 (s, 1H), 8.52 (d, J=4.0 Hz, 1H),8.22 (s, 1H), 7.76 (td, J=7.7, 1.8 Hz, 1H), 7.36-7.21 (m, 2H), 4.58 (d,J=6.0 Hz, 2H), 3.92-3.82 (m, 1H), 3.84-3.71 (m, 1H), 3.68-3.42 (m, 3H),2.34-2.25 (m, 1H), 2.27-2.11 (m, 1H)

HPLCMS (Method A): [m/z]: 389.15 [M+H]⁺

N-[(3-Fluoropyridin-2-yl)methyl]-2-(pyrrolidin-3-yl)-1,3-thiazole-4-carboxamidedihydrochloride (153)

In a similar fashion using general procedure 2, 12M HCl (6 ml) andtert-butyl3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)pyrrolidine-1-carboxylate(151) (1.27 g, 2.87 mmol) in MeOH (25 ml) at 40° C. for 4 h gave thetitle compound (1.11 g, 96.7%) as a cream foam. Compound was used in thenext step without further purification.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.58 (dd, J=5.4, 1.2 Hz, 1H),8.28-8.18 (m, 2H), 7.87 (dt, J=8.6, 4.8 Hz, 1H), 4.94 (d, J=1.3 Hz, 2H),4.25-4.11 (m, 1H), 3.82 (dd, J=11.8, 4.6 Hz, 1H), 3.72-3.43 (m, 3H),2.67-2.46 (m, 1H), 2.39-2.23 (m, 1H)

HPLCMS (Method A): [m/z]: 307.05 [M+H]⁺

N-(Pyridin-2-ylmethyl)-2-(pyrrolidin-3-yl)-1,3-thiazole-4-carboxamidedihydrochloride (154)

In a similar fashion using general procedure 2, 12M HCl (7 ml) andtert-butyl3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}pyrrolidine-1-carboxylate(152) (1.54 g, 3.35 mmol) in MeOH (30 ml) at 40° C. for 4 h gave thetitle compound (1.42 g, 99%) as a pale brown foam. Compound was used inthe next step without further purification.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.77 (d, J=5.9 Hz, 1H), 8.65-8.54(m, 1H), 8.25 (s, 1H), 8.12 (d, J=8.1 Hz, 1H), 7.99 (t, J=6.8 Hz, 1H),4.96 (s, 2H), 4.17 (ddd, J=11.5, 7.3, 4.3 Hz, 1H), 3.86 (dd, J=11.9, 4.2Hz, 1H), 3.79-3.41 (m, 3H), 2.56 (dq, J=13.4, 8.3 Hz, 1H), 2.41-2.21 (m,1H)

HPLCMS (Method A): [m/z]: 289.05 [M−H]⁺

N-[(3-Fluoropyridin-2-yl)methyl]-2-(1-{2-[(2-nitrophenyl)carbamoyl]ethyl}pyrrolidin-3-yl)-1,3-thiazole-4-carboxamide(155)

In a similar fashion to general procedure 8,N-[(3-fluoropyridin-2-yl)methyl]-2-(pyrrolidin-3-yl)-1,3-thiazole-4-carboxamidedihydrochloride (153) (1.11 g, 2.78 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (0.59 g, 3.06 mmol), DBU (1.41 ml,9.45 mmol) in MeCN (20 ml) at room temperature for 19 h, gave the titlecompound (1.53 g, 99%) as a yellow oil after work up.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=10.69 (s, 1H), 8.67 (t, J=5.7 Hz, 1H),8.38 (dt, J=4.6, 1.4 Hz, 1H), 8.11 (s, 1H), 7.96 (dd, J=8.2, 1.5 Hz,1H), 7.79 (dd, J=8.2, 1.2 Hz, 1H), 7.73-7.67 (m, 2H), 7.40 (dt, J=8.6,4.4 Hz, 1H), 7.33 (ddd, J=8.5, 7.4, 1.4 Hz, 1H), 4.63 (d, J=4.6 Hz, 2H),3.87-3.77 (m, 1H), 2.99 (dd, J=9.2, 7.4 Hz, 1H), 2.88-2.74 (m, 4H),2.70-2.62 (m, 1H), 2.57 (td, J=6.7, 1.9 Hz, 2H), 2.43-2.34 (m, 1H),2.08-1.99 (m, 1H)

HPLCMS (Method A): [m/z]: 499.1 [M+H]⁺

Tert-butyl3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}pyrrolidine-1-carboxylate(Example Compound No. 214)

In a similar fashion to general procedure 8,N-[(3-fluoropyridin-2-yl)methyl]-2-(1-{2-[(2-nitrophenyl)carbamoyl]ethyl}pyrrolidin-3-yl)-1,3-thiazole-4-carboxamide(155) (1.53 g, 2.78 mmol), AcOH (15 ml) and iron powder (0.62 g, 11.11mmol) at 8000 for 2 h, gave the title compound (94 mg, 8%) as a palebrown solid after purification by flash column chromatography (KP—NH,eluting with a grading of 0-25% MeOH/DCM) gave a residue (207 mg) whichwas re-purified by flash column chromatography (KP—NH, eluting with agradient of 0-3% MeOH/DCM).

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.33 (d, J=4.7 Hz, 1H), 7.94 (s,1H), 7.58 (app t, J=9.1 Hz, 1H), 7.47 (br s, 2H), 7.40-7.32 (m, 1H),7.24-7.16 (m, 2H), 4.75 (d, J=1.4 Hz, 2H), 3.87-3.80 (m, 1H), 3.17-3.11(m, 2H), 3.11-2.96 (m, 5H), 2.78-2.69 (m, 1H), 2.48-2.38 (m, 1H),2.18-2.04 (m, 1H)

HPLCMS (Method C): [m/z]: 451.1 [M+H]⁺

2-(1-{2-[(2-Nitrophenyl)carbamoyl]ethyl}pyrrolidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide(156)

In a similar fashion to general procedure 8, DBU (1.52 ml, 10.19 mmol),N-(pyridin-2-ylmethyl)-2-(pyrrolidin-3-yl)-1,3-thiazole-4-carboxamidedihydrochloride (154) (84.6%, 1.28 g, 3.0 mmol) andN-(2-nitrophenyl)prop-2-enamide (D) (0.63 g, 3.3 mmol) in MeCN (25 ml)room temperature for 19 h gave the title compound (1.43 g, 99%) as ayellow oil after purification by flash column chromatography (elutingwith a gradient of 0-12% MeOH/DCM).

¹H NMR (DMSO-d6, 500 MHz): d[ppm]=10.67 (s, 1H), 8.83 (t, J=6.0 Hz, 1H),8.51 (d, J=4.2 Hz, 1H), 8.12 (s, 1H), 7.96 (dd, J=8.2, 1.4 Hz, 1H), 7.82(d, J=8.2 Hz, 1H), 7.74 (td, J=7.7, 1.8 Hz, 1H), 7.69 (td, J=8.5, 8.0,1.5 Hz, 1H), 7.36-7.24 (m, 3H), 4.55 (d, J=6.1 Hz, 2H), 3.87-3.78 (m,1H), 3.04-2.98 (m, 1H), 2.89-2.74 (m, 4H), 2.71-2.65 (m, 1H), 2.57 (td,J=6.7, 1.7 Hz, 2H), 2.44-2.33 (m, 1H), 2.09-2.01 (m, 1H)

HPLCMS (Method A): [m/z]: 481.35 [M+H]⁺

2-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]pyrrolidin-3-yl}-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 215)

In a similar fashion to general procedure 8,2-(1-{2-[(2-nitrophenyl)carbamoyl]ethyl}pyrrolidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide(156) (1.43 g, 2.77 mmol) and iron powder (0.62 g, 11.07 mmol) in AcOH(15 ml) at 80° C. for 2 h, gave the title compound (116 mg, 10%) as anoff-white solid after purification by flash column chromatography (×3)(eluting with a gradient of 0-40% MeOH/DCM followed gradient of 0-3%MeOH/DCM and then a gradient of 0-10% MeOH/DCM).

1H-NMR (Methanol-d4, 500 MHz) d[ppm]=8.48 (d, J=4.4 Hz, 1H), 7.95 (s,1H), 7.79 (app t, J=7.1 Hz, 1H), 7.48 (s, 2H), 7.39 (d, J=7.8 Hz, 1H),7.36-7.26 (m, 1H), 7.25-7.12 (m, 2H), 4.67 (s, 2H), 3.89-3.78 (m, 1H),3.18-3.11 (m, 2H), 3.11-2.96 (m, 5H), 2.73 (q, J=8.6 Hz, 1H), 2.49-2.39(m, 1H), 2.19-2.06 (m, 1H)

HPLCMS (Method C): [m/z]: 433.1 [M+H]⁺

General Scheme 9 Above General Procedure 12: Tert-butyl3-carbamoylazetidine-1-carboxylate (157)

1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (4.96 g, 24.65mmol) and TEA (5.84 ml, 42.0 mmol) were dissolved in THF (60 ml) andcooled to −20° C. Isobutyl chloroformate (4.8 ml, 37.0 mmol) was addedslowly and the reaction mixture stirred at <−10° C. for 15 min. 28%aqueous ammonia (7.46 ml, 394 mmol) was added and the mixture allowed towarm to room temperature and stirred for 1 h. The reaction mixture wasquenched with sat. NaHCO₃(aq) and extracted with DCM (3×100 ml). Thecombined organic extracts were dried (Na₂SO₄), filtered and evaporatedin vacuo. Purification by flash chromatography using a gradient elutionof 20-100% EtOAc/heptane followed by 1-4% MeOH/EtOAc afforded the titlecompound (3.99 g, 81%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.47 (s, 2H), 4.22-4.01 (m, 4H),3.34-3.15 (m, 1H), 1.46 (s, 9H)

HPLCMS (Method A): [m/z]: 222.95 [M+Na]⁺

Tert-butyl 3-carbamoyl-3-methylazetidine-1-carboxylate (158)

In a similar fashion to general procedure 12,1-[(tert-butoxy)carbonyl]-3-methylazetidine-3-carboxylic acid (110 mg,0.51 mmol), TEA (90 mg, 0.87 mmol), isobutyl chloroformate (0.1 ml, 0.77mmol) and NH₃ (28% aqueous solution, 0.15 ml, 10 mmol) in THF (10 ml)gave the title compound (102 mg, 93%) as a white solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=5.63 (s, 1H), 5.37 (s, 1H), 4.21 (d,J=8.4 Hz, 2H), 3.72 (d, J=8.4 Hz, 2H), 1.58 (s, 3H), 1.47 (s, 9H)

HPLCMS (Method A): [m/z]: 237 [M+Na]⁺

Tert-butyl 3-carbamothioylazetidine-1-carboxylate (159)

In a similar fashion to general procedure 11, Lawesson reagent (4.43 g,11.0 mmol), tert-butyl 3-carbamoylazetidine-1-carboxylate (157) (3.99 g,19.9 mmol) in DCM (60 ml) at room temperature for 30 min gave the titlecompound (4.47 g) as a pale yellow residue after being flushed through aplug of silica using a gradient elution of 10-80% EtOAc/heptane.

HPLCMS (Method A): [m/z]: 238.9 [M+Na]⁺

Tert-butyl 3-carbamothioyl-3-methylazetidine-1-carboxylate (160)

In a similar fashion to general procedure 11, tert-butyl3-carbamoyl-3-methylazetidine-1-carboxylate (158) (1.0 g, 4.67 mmol) andLawesson reagent (1.04 g, 3.0 mmol) in DCM (30 ml) gave the titlecompound (1.07 g) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.47 (s, 1H), 6.88 (s, 1H), 4.33 (d,J=8.3 Hz, 2H), 3.81 (d, J=8.3 Hz, 2H), 1.72 (s, 3H), 1.47 (s, 9H)

HPLCMS (Method A): [m/z]: 253.05 [M+Na]⁺

Ethyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazole-4-carboxylate(161)

In a similar fashion to general procedure 1, tert-butyl3-carbamothioylazetidine-1-carboxylate (159) (4.47 g, 20.67 mmol), ethyl3-bromo-2-oxopropanoate (2.85 ml, 22.73 mmol) and calcium carbonate(1.12 g, 11.0 mmol) in EtOH (40 ml) afforded the title compound (3.54 g,54%) as a yellow oil after purification by flash chromatography using agradient elution from 10-50% EtOAc/heptane.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.49 (s, 1H), 4.37-4.23 (m, 5H), 4.00(m, 2H), 1.41 (s, 9H), 1.31 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 335 [M+Na]⁺

Ethyl2-{1-[(tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-1,3-thiazole-4-carboxylate(162)

In a similar fashion to general procedure 1, tert-butyl3-carbamothioyl-3-methylazetidine-1-carboxylate (160) (0.82 g, 3.56mmol), ethyl 3-bromo-2-oxopropanoate (0.49 ml, 4.0 mmol) and calciumcarbonate (0.2 g, 2.0 mmol) in EtOH (20 ml) gave the title compound (1.0g) as a pale yellow oil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.14 (s, 1H), 4.44 (q, J=7.1 Hz, 2H),4.39 (d, J=8.0 Hz, 2H), 3.98 (d, J=8.0 Hz, 2H), 1.83 (s, 3H), 1.48 (s,9H), 1.43 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 349.15 [M+Na]⁺

2-{1-[(Tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazole-4-carboxylicacid (163)

In a similar fashion to general procedure 5, ethyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazole-4-carboxylate(161) (2.52 g, 7.91 mmol) and LiOH (0.57 g, 23.72 mmol) in THF (40 ml)and water (40 ml) afforded the title compound (2.23 g, 87% purity, 86%)as an orange solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=13.03 (s, 1H), 8.40 (s, 1H), 4.31-4.23(m, 2H), 4.23-4.17 (m, 1H), 4.05-3.93 (m, 2H), 1.40 (s, 9H)

HPLCMS (Method A): [m/z]: 306.85 [M+Na]⁺

2-{1-[(Tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-1,3-thiazole-4-carboxylicacid (164)

In a similar fashion to general procedure 5, ethyl2-{1-[(tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-1,3-thiazole-4-carboxylate(162) (1.0 g, 3.06 mmol) and LiOH (0.22 g, 10.0 mmol) in THF (30 ml) andwater (15 ml) gave the title compound (853 mg, 93%) as a pale yellowfoam.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.44 (s, 1H), 4.16 (d, J=8.2 Hz, 2H),3.90 (d, J=8.2 Hz, 2H), 1.72 (s, 3H), 1.41 (s, 9H)

HPLCMS (Method A): [m/z]: 321.05 [M+Na]⁺

Tert-butyl3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate(165)

In a similar fashion to general procedure 6,2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazole-4-carboxylicacid (163) (87%, 2.23 g, 6.69 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (1.6 g, 8.03 mmol), DIPEA (4.66 ml, 26.77 mmol) andHATU (3.05 g, 8.03 mmol) in DCM (40 ml) afforded the title compound(2.51 g, 82% purity, 79%) as an orange oil after purification by flashcolumn chromatography using an elution gradient 20-100% EtOAc/heptane.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.79 (t, J=5.7 Hz, 1H), 8.38 (dt,J=4.6, 1.4 Hz, 1H), 8.24 (s, 1H), 7.76-7.62 (m, 1H), 7.46-7.35 (m, 1H),4.66 (dd, J=5.7, 1.5 Hz, 2H), 4.34-4.17 (m, 3H), 4.16-4.05 (m, 2H), 1.39(s, 9H)

HPLCMS (Method A): [m/z]: 393 [M+H]⁺

Tert-butyl3-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol-2-yl]azetidine-1-carboxylate(166)

In a similar fashion to general procedure 6,2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazole-4-carboxylicacid (163) (300 mg, 1.06 mmol), 5H,6H,7H-cyclopenta[b]pyridin-7-aminedihydrochloride (284 mg, 1.37 mmol), DIPEA (0.61 ml, 3.5 mmol) and HATU(0.52 g, 1.4 mmol) in DCM (20 ml) afforded the crude title compound(1.32 g, 30% purity, 94%) which was used into the next step withoutpurification.

HPLCMS (Method A): [m/z]: 401.1 [M+H]⁺

Tert-butyl3-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate(167)

In a similar fashion to general procedure 6,2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazole-4-carboxylicacid (163) (364 mg, 1.28 mmol), (3-chloropyridin-2-yl)methanaminedihydrochloride (359 mg, 1.66 mmol), DIPEA (0.74 ml, 4.2 mmol) and HATU(0.63 g, 1.7 mmol) in DCM (20 ml) afforded the title compound (493 mg,94%) as a pale yellow oil after purification by flash columnchromatography (eluting with a gradient of 0-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.79 (t, J=5.5 Hz, 1H), 8.51 (dd,J=4.7, 1.4 Hz, 1H), 8.27 (s, 1H), 7.96 (dd, J=8.1, 1.4 Hz, 1H), 7.39(dd, J=8.1, 4.7 Hz, 1H), 4.70 (d, J=5.5 Hz, 2H), 4.38-4.18 (m, 3H), 4.09(q, J=3.9 Hz, 2H), 1.41 (s, 9H)

HPLCMS (Method A): [m/z]: 409.05 [M+H]⁺

Tert-butyl3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-3-methylazetidine-1-carboxylate(168)

In a similar fashion to general procedure 6,2-{1-[(tert-butoxy)carbonyl]-3-methylazetidin-3-yl}-1,3-thiazole-4-carboxylicacid (164) (546 mg, 1.83 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (400 mg, 2.01 mmol), DIPEA (1.05 ml, 6.0 mmol) andHATU (830 mg, 2.0 mmol) in DCM (20 ml) gave the crude title compound(824 mg) as a pale yellow oil. The crude material was used in the nextstep without further purification.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.38-8.33 (m, 1H), 8.28 (s, 1H), 8.02(s, 1H), 7.37-7.31 (m, 1H), 7.23-7.17 (m, 1H), 4.81-4.76 (m, 2H), 4.30(d, J=7.5 Hz, 2H), 3.88 (d, J=7.5 Hz, 2H), 1.52 (s, 3H), 1.40 (s, 9H)

HPLCMS (Method A): [m/z]: 407.2 [M+H]⁺

2-(Azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (169)

In a similar fashion to general procedure 4, tert-butyl3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate(165) (82%, 2.51 g, 5.26 mmol) and 12 M HCl (8.8 ml) in MeOH (25 ml)afforded the title compound (2.26 g, 85% purity, quant.) as a lightbrown solid.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.56 (d, J=5.2 Hz, 1H), 8.27 (s,1H), 8.24-8.07 (m, 1H), 7.87-7.73 (m, 1H), 4.96-4.91 (m, 2H), 4.57-4.41(m, 5H)

HPLCMS (Method A): [m/z]: 292.95 [M+H]⁺

2-(Azetidin-3-yl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazole-4-carboxamide(170)

In a similar fashion to general procedure 4, crude tert-butyl3-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1,3-thiazol-2-yl]azetidine-1-carboxylate(166) (1.32 g, 30% purity, 1.06 mmol) and 12 M HCl (1 ml) in MeOH (10ml) afforded the title compound (322 mg, quant.) as a white solid afterpurification using an SCX-2 cartridge, rinsing with DCM and MeOH, thenelution with 7 N ammonia in MeOH.

HPLCMS (Method A): [m/z]: 300.95 [M+H]⁺

2-(Azetidin-3-yl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(171)

In a similar fashion to general procedure 4, tert-butyl3-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate(167) (423 mg, 1.03 mmol) and 12 M HCl (2 ml) in MeOH (30 ml) affordedthe title compound (330 mg, 99%) as a white solid after purificationusing an SCX-2 cartridge, rinsing with DCM and MeOH, then elution with 7N ammonia in MeOH.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.71 (t, J=5.5 Hz, 1H), 8.52 (dd,J=4.7, 1.4 Hz, 1H), 8.24 (s, 1H), 7.96 (dd, J=8.0, 1.4 Hz, 1H), 7.39(dd, J=8.0, 4.7 Hz, 1H), 4.70 (d, J=5.5 Hz, 2H), 4.24 (m, 1H), 3.92-3.87(m, 2H), 3.76-3.73 (m, 2H)

HPLCMS (Method A): [m/z]: 308.95 [M+H]⁺

N-[(3-Fluoropyridin-2-yl)methyl]-2-(3-methylazetidin-3-yl)-1,3-thiazole-4-carboxamide(172)

In a similar fashion to general procedure 4, tert-butyl3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-3-methylazetidine-1-carboxylate(168) (824 mg, 2.03 mmol) and 12 M HCl (2 ml) in MeOH (20 ml) gave thetitle compound (476 mg, 74%) after purification using an SCX-2cartridge, rinsing with DCM and MeOH, then elution with 7 N ammonia inMeOH.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.71 (t, J=5.7 Hz, 1H), 8.39 (dt,J=4.6, 1.3 Hz, 1H), 8.21 (s, 1H), 7.71 (ddd, J=10.0, 8.3, 1.3 Hz, 1H),7.46-7.36 (m, 1H), 4.68 (m, 2H), 3.85 (d, J=7.5 Hz, 2H), 3.52 (d, J=7.5Hz, 2H), 1.72 (s, 3H)

HPLCMS (Method A): [m/z]: 307.20 [M+H]⁺

2-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 193)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (169) (85%, 2.26 g, 5.26 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (1.21 g, 6.31 mmol) and DBU (2.35ml, 15.77 mmol) in MeCN (30 ml) afforded a crude intermediate which wasfurther reacted with iron powder (0.51 g, 9.0 mmol) and AcOH (5 ml) toafford the title compound (122 mg, 7%) as a cream solid afterpurification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.33 (dt, J=4.7, 1.3 Hz, 1H), 8.12(s, 1H), 7.62-7.56 (m, 1H), 7.53-7.47 (m, 2H), 7.39-7.34 (m, 1H),7.22-7.17 (m, 2H), 4.79 (d, J=1.7 Hz, 2H), 4.11-4.03 (m, 1H), 3.80 (t,J=7.9 Hz, 2H), 3.55-3.50 (m, 2H), 3.07-3.02 (m, 2H), 3.01-2.96 (m, 2H)

HPLCMS (Method G): [m/z]: 437 [M+H]⁺

2-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazole-4-carboxamide(Example Compound No. 194)

In a similar manner to general procedure 8,2-(azetidin-3-yl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1,3-thiazole-4-carboxamide(170) (322 mg, 1.07 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (227 mg,1.18 mmol) and DBU (0.21 ml, 1.4 mmol) in MeCN (10 ml) gave a crudeintermediate which was further reacted with iron powder (0.15 g, 2.6mmol) in AcOH (4 ml) to afford the title compound (139 mg, 48%) as awhite solid after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.35 (d, J=5.0 Hz, 1H), 8.15 (s,1H), 7.78-7.74 (m, 1H), 7.50 (br s, 2H), 7.29 (dd, J=7.6, 5.0 Hz, 1H),7.24-7.18 (m, 2H), 5.58 (t, J=8.3 Hz, 1H), 4.05 (tt, J=7.9, 6.4 Hz, 1H),3.77 (t, J=7.9 Hz, 2H), 3.56-3.49 (m, 2H), 3.11 (ddd, J=16.3, 9.1, 2.8Hz, 1H), 3.05-3.00 (m, 3H), 3.00-2.94 (m, 2H), 2.73 (m, 1H), 2.11 (m,1H)

HPLCMS (Method C): [m/z]: 445.3 [M+H]⁺

2-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 195)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(171) (330 mg, 1.07 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (226 mg,1.18 mmol) and DBU (0.21 ml, 1.4 mmol) in MeCN (10 ml) gave the requiredcrude intermediate which was further reacted with iron powder (150 mg,2.6 mmol) in AcOH (4 ml) to afford the title compound (80 mg, 27%) as awhite solid after purification by basic prep-HPLC followed by flashcolumn chromatography (eluting with a gradient of 0-12% MeOH/DCM).

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.15(s, 1H), 7.88 (dd, J=8.1, 1.4 Hz, 1H), 7.51 (br s, 2H), 7.32 (dd, J=8.1,4.7 Hz, 1H), 7.24-7.19 (m, 2H), 4.85-4.82 (m, 2H), 4.11 (m, 1H), 3.84(t, J=7.9 Hz, 2H), 3.59-3.53 (m, 2H), 3.10-3.05 (m, 2H), 3.03-2.98 (m,2H)

HPLCMS (Method C): [m/z]: 453.2 [M+H]⁺

2-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]-3-methylazetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 212)

In a similar fashion to general procedure 8,N-[(3-fluoropyridin-2-yl)methyl]-2-(3-methylazetidin-3-yl)-1,3-thiazole-4-carboxamide(172) (476 mg, 1.55 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (328 mg,1.71 mmol) and DBU (0.26 ml, 2 mmol) in MeCN (15 ml) gave the requiredcrude intermediate which was further reacted with iron powder (350 mg,10.0 mmol) in AcOH (5 ml). Purification by basic prep-HPLC followed byflash column chromatography (eluting with a gradient of 0-30% MeOH/DCM)gave the title compound (162 mg, 23%) as a white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.34-8.27 (m, 1H), 8.14 (s, 1H),7.60 (ddd, J=9.7, 8.5, 1.2 Hz, 1H), 7.51 (s, 2H), 7.37-7.32 (m, 1H),7.24-7.18 (m, 2H), 4.80 (d, J=1.3 Hz, 2H), 3.78 (d, J=7.7 Hz, 2H), 3.47(d, J=7.7 Hz, 2H), 3.10 (t, J=7.2 Hz, 2H), 3.00 (t, J=7.2 Hz, 2H), 1.78(s, 3H)

HPLCMS (Method C): [m/z]: 451.1 [M+H]⁺

General Scheme 10 Above Methyl 2,2-dimethyl-3-oxopropanoate (173)

To an ice-cooled (0° C.) solution of methyl3-hydroxy-2,2-dimethylpropanoate (1.45 ml, 11.35 mmol) and TEA (4.75 ml,34.05 mmol) in DCM (45 ml) and DMSO (8 ml, 113.5 mmol) was addedpyridine sulfur trioxide complex (5.42 g, 34.05 mmol). The resultingmixture was stirred at room temperature for 22 h. The reaction wasquenched with saturated NH₄Cl (30 ml). The layers were separated and theaqueous layer was extracted with DCM (40 ml). The organic layer waswashed sequentially with 2M HCl (2×20 ml) and brine (15 ml), dried(MgSO₄), filtered and evaporated to give the title compound (0.35 g,99%) as an orange oil.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=9.66 (s, 1H), 5.30 (s, 1H), 3.75 (s,3H), 1.35 (s, 6H)

Methyl3-{[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoate(174)

DIPEA (1.8 ml, 10.32 mmol) was added to2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (103) (0.97 g, 2.58 mmol) and methyl2,2-dimethyl-3-oxopropanoate (173) (0.52 g, 3.36 mmol) in MeOH (20 ml).The reaction was stirred at room temperature for 18 h. The reaction wascooled to 0° C. and NaBH₄ (146 mg, 3.87 mmol) was added portionwise. Thereaction was allowed to warm to room temperature and stirred for 3.5 h.The solvent evaporated and water (10 ml) added. The aqueous layerextracted with EtOAc (3×20 ml). The combined organic layers were dried(MgSO4), filtered and evaporated to give an orange oil (1.1 g).Purification by flash column chromatography (eluting with a gradient of0-15% MeOH/DCM) gave the title compound (0.95 g, 79%) as a pale yellowoil.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.43-8.38 (m, 2H), 8.02 (s, 1H),7.45-7.36 (m, 1H), 7.26-7.20 (m, 1H), 4.85 (dd, J=5.3, 1.7 Hz, 2H), 3.63(s, 3H), 3.20 (t, J=5.6 Hz, 2H), 3.10 (t, J=5.8 Hz, 2H), 2.79 (s, 2H),1.22 (s, 6H)

HPLCMS (Method A): [m/z]: 395.05 [M+H]⁺

3-{[(Tert-butoxy)carbonyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoate(175)

TEA (0.5 ml, 3.62 mmol) was added to methyl3-{[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoate(174) (0.95 g, 2.41 mmol) in DCM (10 ml). The reaction was stirred for 5min at room temperature, di-tert-butyl dicarbonate (0.63 g, 2.9 mmol) inDCM (10 ml) was added dropwise and the reaction stirred at roomtemperature for 20 h. The solvent was evaporated and purification byflash column chromatography (eluting with a gradient of 0-100%EtOAc/heptane) to give the title compound (0.94 g, 90%) as a clear oil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.42 (d, J=4.3 Hz, 2H), 8.01 (s, 1H),7.44-7.37 (m, 1H), 7.26 (m, 1H, obscured by solvent peak), 4.85 (dd,J=5.1, 1.7 Hz, 2H), 3.70 (s, 3H), 3.55 (t, J=7.0 Hz, 2H), 3.48-3.41 (brm, 2H), 3.31-3.14 (m, 2H), 1.45 (s, 9H), 1.19 (s, 6H)

HPLCMS (Method A): [m/z]: 495.15 [M+H]⁺

3-{[(Tert-butoxy)carbonyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoicacid (176)

In a similar fashion using general procedure 5, LiOH (0.27 g, 11.1 mmol)and3-{[(tert-butoxy)carbonyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoate(175) (0.94 g, 1.85 mmol) in THF (6 ml)/water (1.5 ml) gave the titlecompound (0.91 g, 96%) as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.41 (s, 1H), 8.63 (s, 1H), 8.39 (s,1H), 8.17 (s, 1H), 7.71 (ddd, J=10.0, 8.3, 1.2 Hz, 1H), 7.41 (dt, J=8.6,4.4 Hz, 1H), 4.67 (dd, J=5.6, 1.3 Hz, 2H), 3.53 (t, J=7.1 Hz, 2H), 3.38(s, 2H), 3.23 (t, J=7.1 Hz, 2H), 1.34 (s, 9H), 1.07 (s, 6H)

HPLCMS (Method A): [m/z]: 481.15 [M+H]⁺

Tert-butylN-{2-[(2-aminophenyl)carbamoyl]-2,2-dimethylethyl}-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(177)

In a similar fashion using general procedure 6,3-{[(tert-butoxy)carbonyl][2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]amino}-2,2-dimethylpropanoicacid (176) (0.5 g, 0.98 mmol), benzene-1,2-diamine (0.14 g, 1.3 mmol),TEA (0.18 ml, 1.3 mmol) and HATU (0.49 g, 1.3 mmol) in DMF (10 ml) gavethe title compound (0.51 g, 83%) as a yellow oil after purification byflash column chromatography using a gradient of 0-100% EtOAc/heptane.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.84 (s, 1H), 8.61 (s, 1H), 8.37 (d,J=4.5 Hz, 1H), 8.16 (s, 1H), 7.70 (ddd, J=10.1, 8.3, 1.2 Hz, 1H), 7.41(dt, J=8.6, 4.4 Hz, 1H), 7.02-6.86 (m, 2H), 6.78-6.68 (m, 1H), 6.57-6.45(m, 1H), 4.66 (d, J=4.4 Hz, 2H), 3.55 (t, J=6.9 Hz, 2H), 3.50 (s, 2H),3.24 (t, J=6.9 Hz, 2H), 1.35 (s, 9H), 1.21 (s, 6H)

HPLCMS (Method A): [m/z]: 571.2 [M+H]⁺

Tert-butylN-[2-(1H-1,3-benzodiazol-2-yl)-2-methylpropyl]-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(178)

Tert-butylN-{2-[(2-aminophenyl)carbamoyl]-2,2-dimethylethyl}-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(177) (260 mg, 0.415 mmol) in glacial AcOH (4 ml) was heated to 80° C.for 35 min. The reaction was cooled, concentrated in vacuo and theresidue partitioned between EtOAc (10 ml) and saturated K₂COO₃ (10 ml).The layers were separated and the aqueous layer extracted with EtOAc(2×10 ml). The combined organic layers were dried (Na₂SO₄), filtered andevaporated to give a brown oil. Purification by flash columnchromatography (KP—NH column eluting with a gradient of 0-100%DCM/heptane) gave the title compound (172 mg, 71%) as a pale brown oil.

¹H-NMR (CDCl₃, 500 MHz): d[ppm]=8.43 (br s, 1H), 8.42 (dt, J=4.6 and 1.2Hz, 2H), 7.99 (s, 1H), 7.82-7.69 (m, 1H), 7.47-7.42 (m, 1H), 7.40-7.34(m, 1H), 7.25-7.18 (m, 2H), 4.91 (d, J=4.5 Hz, 2H), 3.75-3.69 (br m,2H), 3.59-3.39 (br m, 2H), 3.11 (t, J=6.3 Hz, 2H), 1.59 (s, 9H), 1.45(s, 6H)

HPLCMS (Method A): [m/z]: 553.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)-2-methylpropyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 199)

In a similar fashion to general procedure 2, TFA (2 ml) was added totert-butylN-{2-[(2-aminophenyl)carbamoyl]-2,2-dimethylethyl}-N-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(178) (172 mg, 0.25 mmol) in DCM (2 ml) and stirred at room temperaturefor 3 h, to give the title compound (79 mg, 70%) as a beige solid afterpurification by Isolute SCX-2 cartridge, eluted with DCM (2 CV),DCM/MeOH (1:1, 1 CV), MeOH (2 CV) and then 7M NH₃ in MeOH (2 CV).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.01 (s, 1H), 8.62 (t, J=5.7 Hz, 1H),8.37 (dt, J=4.7 and 1.5 Hz, 1H), 8.02 (s, 1H), 7.74-7.63 (m, 1H),7.53-7.35 (m, 2H), 7.42-7.38 (m, 1H), 7.14-7.06 (m, 2H), 4.64 (dd,J=5.6, 1.4 Hz, 2H), 3.11 (t, J=6.5 Hz, 2H), 2.91-2.87 (m, 4H), 1.39 (s,6H)

HPLCMS (Method D): [m/z]: 453.2 [M+H]⁺

2-(1H-1,3-Benzodiazol-2-yl)acetic acid (179)

2M NaOH (90.7 ml, 181 mmol) was added to2-(1H-1,3-benzodiazol-2-yl)acetonitrile (9.5 g, 60.4 mmol). The reactionheated at 100° C. for 3 h. The reaction mixture was cooled to roomtemperature and acidified to pH 5-6 with 4 M HCl. The resultingprecipitate was filtered, washed with water and dried in vacuo to givethe title compound (9.7 g, 77%) as light brown solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=7.52-7.46 (m, 1H), 7.45-7.39 (m, 1H),7.17-7.11 (m, 1H), 7.11-7.06 (m, 1H), 2.47 (s, 2H)

HPLCMS (Method F): [m/z]: 177.0 [M+H]⁺

Methyl 2-(1H-1,3-benzodiazol-2-yl)acetate (180)

Thionyl dichloride (0.7 ml, 9.65 mmol) was added dropwise to anice-cooled (0° C.) suspension of 2-(1H-1,3-benzodiazol-2-yl)acetic acid(179) (0.7 g, 3.97 mmol) in MeOH (30 ml). The reaction mixture wasallowed to warm to room temperature and stirred for 18 h. The mixturewas poured onto saturated NaHCO₃ (40 ml) and extracted with DCM (3×20ml). The combined organic layers were washed with brine (30 ml), dried(NaSO₄), filtered and evaporated to give the title compound (0.65 g,86%) as a cream solid.

1H-NMR (CDCl3, 500 MHz): d[ppm]=10.10 (br s, 1H), 7.72 (br s, 1H), 7.46(br s, 1H), 7.29-7.23 (m, 2H), 4.09 (s, 2H), 3.82 (s, 3H)

HPLCMS (Method F): [m/z]: 191.2 [M+H]⁺

Tert-butyl 2-(2-methoxy-2-oxoethyl)-1H-1,3-benzodiazole-1-carboxylate(181)

In a similar fashion to general procedure 4, methyl2-(1H-1,3-benzodiazol-2-yl)acetate (180) (650 mg, 3.42 mmol), TEA (0.5ml, 3.59 mmol), Boc₂O (890 mg, 4.11 mmol) and DMAP (84 mg, 0.68 mmol) inTHF (30 ml) at room temperature for 18 h, gave the title compound (940mg, 95%) as a cream solid after purification by flash columnchromatography (eluting with a gradient of 0-100% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=7.96-7.90 (m, 1H), 7.74-7.68 (m, 1H),7.38-7.31 (m, 2H), 4.28 (s, 2H), 3.73 (s, 3H), 1.69 (s, 9H)

HPLCMS (Method A): [m/z]: 291 [M+H]⁺

Tert-butyl2-(1,1-difluoro-2-methoxy-2-oxoethyl)-1H-1,3-benzodiazole-1-carboxylate(182)

KHMDS (1.5 g, 7.61 mmol) in THF (15 ml) was cooled to −78° C. tert-Butyl2-(2-methoxy-2-oxoethyl)-1H-1,3-benzodiazole-1-carboxylate (181) (0.74g, 2.54 mmol) was added and the mixture was stirred at −78° C. for 45min. A combined mixture of 18-crown-6 (2.01 g, 7.61 mmol) andN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (2.2 g, 7.1 mmol) wasadded. The mixture was stirred at −78° C. for 30 min. Additional KHMDS(0.75 g, 3.76 mmol) was added and stirred for 20 min. AdditionalN-fluoro-N-(phenylsulfonyl)benzenesulfonamide (1.1 g, 3.49 mmol) and18-crown-6 (1 g, 3.78 mmol) were added. The reaction mixture was thenallowed to slowly warm to room temperature and stirred for 18 h to givea ratio of 1.6:1 bis:mono fluorinated products. Saturated NH₄Cl (12 ml)was added followed by water (20 ml). The organic and aqueous layers wereseparated. The aqueous layer was extracted with EtOAc (3×50 ml). Thecombined organic layers were washed with brine (100 ml), dried (NaSO₄),filtered and evaporated to give a pink semi-solid (3 g). Purification byflash column chromatography (eluting with a gradient of 0-50%TBME/heptane followed by 100% TBME) gave the title compound (0.47 g,48%) as a yellow oil which solidified on standing.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.00-7.81 (m, 2H), 7.55-7.34 (m, 2H),3.91 (s, 3H), 1.70 (s, 9H).

HPLCMS (Method A): [m/z]: 226.9 [M-BOC+H]⁺

Tert-butyl2-(1,1-difluoro-2-hydroxy-2-methoxyethyl)-1H-1,3-benzodiazole-1-carboxylate(183)

NaBH₄ (44 mg, 1.16 mmol) was added to an ice-cooled (00) solution oftert-butyl2-(1,1-difluoro-2-methoxy-2-oxoethyl)-1H-1,3-benzodiazole-1-carboxylate(182) (295 mg, 0.76 mmol) in EtOH (3.5 ml). The reaction was stirred at0° C. for 1.5 h, quenched with dropwise addition of 1 M HCl (0.5 ml).Water (10 ml) was added and the aqueous layer extracted with EtOAc (3×10ml). The combined organic layers dried (NaSO₄), filtered and evaporatedto give a white solid (300 mg). Purification by flash columnchromatography (eluting with a gradient of 0-40% EtOAc/heptane) gave thetitle compound (185 mg, 59%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.03-7.77 (m, 1H), 7.63-7.31 (m, 3H),6.17 (dd, J=6.4, 4.9 Hz, 1H), 3.69 (s, 3H), 1.52 (s, 9H)

HPLCMS (Method A): [m/z]: 329.05 [M+H]⁺

4-(2-{[2-(1H-1,3-Benzodiazol-2-yl)-2,2-difluoroethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-2-carboxamide(Example Compound No. 196)

Tert-Butyl2-(1,1-difluoro-2-hydroxy-2-methoxyethyl)-1H-1,3-benzodiazole-1-carboxylate(183) (160 mg, 0.4 mmol),2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(103) (136 mg, 0.49 mmol) and activated molecular sieves in dry toluene(3 ml) was heated to 125° C. for 18 h. The reaction was cooled to roomtemperature and NaBH₄ (40 mg, 1.06 mmol) was added followed by EtOH (4ml). The reaction mixture was stirred for 1 h. The reaction was quenchedwith dropwise addition of 1 M HCl (10 drops). Once effervescence ceased,water (10 ml) was added and using 2M K₂CO₃, the pH was adjusted to 10.The mixture was filtered and the aqueous layer extracted with EtOAc(3×20 ml).

The combined organic layers dried (NaSO₄), filtered and evaporated togive a brown oily solid (176 mg). Purification by flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM) gave a brownsolid (40 mg). Further purification by basic prep HPLC gave a yellow oil(21 mg). Re-purification by flash column chromatography (eluting with agradient of 0-5% EtOH/DCM) gave the title compound (12 mg, 6%) as a paleyellow solid.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.38-8.32 (m, 1H), 7.90 (s, 1H),7.65-7.55 (m, 3H), 7.42-7.36 (m, 1H), 7.36-7.30 (m, 2H), 4.73 (d, J=1.6Hz, 2H), 3.60 (t, J=14.0 Hz, 2H), 3.20-3.08 (m, 4H)

HPLCMS (Method D): [m/z]: 461.2 [M+H]⁺

General Scheme 11 Above General Procedure 12: Ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylate(184)

A solution of ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (1)(2 g, 6.66 mmol) and hexachloroethane (1.49 g, 6.32 mmol) in THF (140ml) was cooled to −78° C. 2 M NaHMDS (7.0 ml, 14.0 mmol) was addeddropwise. The reaction mixture was stirred at −78° C. for 1 h, quenchedwith sat. NH₄Cl (aq) and allowed to warm to room temperature. Themixture was filtered and the residue was rinsed with THF (50 ml). Thefiltrates were evaporated in vacuo and the residue was partitionedbetween EtOAc and sat. NH₄Cl (aq). The organic layer was separated,dried (MgSO₄) and concentrated in vacuo. Purification by silica flashchromatography (eluting with a gradient of 0-30% EtOAc/DCM) gave thetitle compound (1.47 g, 65%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=4.91 (s, 1H), 4.45 (q, J=7.1 Hz, 2H),3.55 (q, J=6.3 Hz, 2H), 3.18 (t, J=6.4 Hz, 2H), 1.49-1.39 (m, 12H)

HPLCMS (Method A): [m/z]: 356.95 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylicacid (185)

In a similar fashion using general procedure 5, LiOH (739 mg, 30.84mmol) and ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylate(184) (1.47 g, 4.41 mmol) in THF (30 ml)/water (10 ml) gave the titlecompound (1.35 g, quant.) as a yellow oil. The compound was used in thenext step without further purification.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=4.92 (s, 1H), 3.58 (q, J=5.7 Hz, 2H),3.18 (t, J=5.8 Hz, 2H), 1.46 (s, 9H)

HPLCMS (Method A): [m/z]: 328.9 [M+H]⁺

Tert-butylN-[2-(5-chloro-4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(186)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylicacid (185) (800 mg, 2.61 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (623 mg, 3.13 mmol), DIPEA (1.5 ml, 10.0 mmol),HATU (1.19 g, 3.0 mmol) in DCM (30 ml) gave the title compound (1.08 g,80%) as a white solid after purification by flash column chromatography(eluting with a gradient of 0-60% EtOAc/heptane). Compound was used inthe next step without further purification.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.49-8.39 (m, 2H), 7.44 (ddd, J=9.4,8.4, 1.3 Hz, 1H), 7.34-7.23 (m, 3H), 4.94 (s, 1H), 4.84 (dd, J=5.1, 1.7Hz, 2H), 3.59 (q, J=6.3 Hz, 2H), 3.15 (t, J=6.4 Hz, 2H), 1.46 (s, 9H)

HPLCMS (Method A): [m/z]: 415 [M+H]⁺

Tert-butylN-[2-(5-chloro-4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(187)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylicacid (185) (220 mg, 0.72 mmol), (3-chloropyridin-2-yl)methanaminedihydrochloride (154.55 mg, 0.72 mmol), DIPEA (0.26 ml, 2 mmol), HATU(0.33 g, 0.85 mmol) in tetrahydrofuran (10 ml)/DMF (2 ml) gave the titlecompound (360 mg, quant.) as a white solid after purification by flashcolumn chromatography (eluting with a gradient of 20-60% EtOAc/heptane).

Compound was used in the next step without further purification.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.66 (s, 1H), 8.56-8.52 (m, 1H), 7.74(dd, J=8.0, 1.4 Hz, 1H), 7.24 (dd, J=8.0, 4.7 Hz, 1H), 4.98 (s, 1H),4.85 (d, J=4.8 Hz, 2H), 3.61 (q, J=6.1 Hz, 2H), 3.17 (t, J=6.3 Hz, 2H),1.46 (s, 9H).

HPLCMS (Method A): [m/z]: 431.1 [M+H]+

Tert-butylN-(2-{5-chloro-4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(188)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylicacid (185) (216 mg, 0.7 mmol), pyridin-2-ylmethanamine (0.09 ml, 0.84mmol), DIPEA (0.26 ml, 1 mmol), HATU (0.32 g, 0.84 mmol) intetrahydrofuran (10 ml) were stirred at room temperature. Furtherpyridin-2-ylmethanamine (0.09 ml, 0.84 mmol), DIPEA (0.26 ml, 0 mol) andHATU (0.32 g, 0 mol) were added and the reaction continued. The titlecompound (227 mg, 78%) was isolated as a brown oil after purification byflash column chromatography (eluting with a gradient of 5-100%EtOAc/heptane). Compound was used in the next step without furtherpurification.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.50 (d, J=4.4 Hz, 1H), 7.81 (td,J=7.8, 1.5 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.36-7.27 (m, 1H), 4.73 (s,3H), 4.68 (s, 2H), 3.13 (t, J=6.4 Hz, 2H), 1.41 (s, 9H).

HPLCMS (Method A): [m/z]: 397.10 [M+H]⁺

Tert-butylN-(2-{5-chloro-4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(189)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylicacid (185) (220 mg, 0.72 mmol), pyridazin-3-ylmethanamine (0.12 g, 1mmol), DIPEA (0.31 ml, 2 mmol), HATU (0.41 g, 1 mmol) in DCM (20 ml)gave the title compound (278 mg, 91%) as a yellow residue afterpurification by flash column chromatography (eluting with a gradient of50-100% EtOAc/heptane, then 2-6% methanol/ethyl acetate). Compound wasused in the next step without further purification.

HPLCMS (Method A): [m/z]: 398.05 [M+H]⁺

Tert-butylN-(2-{5-chloro-4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(190)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylicacid (185) (579 mg, 1.54 mmol), 1-(pyrimidin-2-yl)methanamine (0.14 g,1.28 mmol), DIPEA (0.67 ml, 3.85 mmol), HATU (0.585 g, 1.54 mmol) intetrahydrofuran (10 ml)/DMF (2 ml) gave the title compound (0.483 g,73%) as a white solid after purification by flash column chromatography(eluting with a gradient of 50-100% EtOAc/heptane). Compound was used inthe next step without further purification.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.83-8.79 (m, 1H), 8.78 (d, J=4.9 Hz,2H), 7.41 (t, J=4.9 Hz, 1H), 7.11-7.05 (m, 1H), 4.64 (d, J=5.9 Hz, 2H),3.09 (t, J=6.6 Hz, 2H), 1.37 (s, 9H).

HPLCMS (Method A): [m/z]: 398 [M+H]⁺

Tert-butylN-[2-(5-chloro-4-{[(5-methylpyrimidin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(191)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-chloro-1,3-thiazole-4-carboxylicacid (185) (556 mg, 1.48 mmol), (5-methylpyrimidin-2-yl)methanamine(0.14 g, 1.14 mmol), DIPEA (0.396 ml, 2.274 mmol), HATU (0.562 g, 1.478mmol) in tetrahydrofuran (10 ml)/DMF (2 ml) gave the title compound (577mg, 92%) as a colourless oil after purification by flash columnchromatography (eluting with a gradient of 70-100% EtOAc/heptane).Compound was used in the next step without further purification.

1H-NMR (DMSO-d6, 500 MHz) δ 8.77 (t, J=5.8 Hz, 1H), 8.63 (s, 2H), 7.08(s, 1H), 4.60 (d, J=5.9 Hz, 2H), 3.09 (t, J=6.6 Hz, 2H), 2.27 (s, 3H),1.37 (s, 9H).

HPLCMS (Method A): [m/z]: 412.05 [M+H]⁺

2-(2-Aminoethyl)-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(192)

In a similar fashion using general procedure 2, 12M HCl (8 ml) andtert-butylN-[2-(5-chloro-4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(186) (1 g, 2.41 mmol) in MeOH (40 ml) at room temperature gave thetitle compound (703 mg, 93%) as a white solid after purification bySCX-2 cartridge (gradient elution 100% DCM, followed by 100% MeOH andthen 7 N NH₃/MeOH).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.73 (t, J=5.6 Hz, 1H), 8.40 (dt,J=4.6, 1.4 Hz, 1H), 7.71 (ddd, J=10.0, 8.3, 1.2 Hz, 1H), 7.42 (dt,J=8.6, 4.4 Hz, 1H), 4.63 (dd, J=5.7, 1.5 Hz, 2H), 3.02 (t, J=6.0 Hz,2H), 2.93 (t, J=6.1 Hz, 2H)

HPLCMS (Method A): [m/z]: 314.95 [M+H]⁺

2-(2-Aminoethyl)-5-chloro-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(193)

In a similar fashion using general procedure 2, 12M HCl (2 ml) andtert-butylN-[2-(5-chloro-4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(187) (360 mg, 0.83 mmol) in MeOH (10 ml) at room temperature gave thetitle compound (320 mg, 95%) as a white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.93 (t, J=6.0 Hz, 1H), 8.52 (dd,J=4.7, 1.3 Hz, 1H), 8.04 (s, 2H), 7.97 (dd, J=8.1, 1.4 Hz, 1H), 7.40(dd, J=8.1, 4.7 Hz, 1H), 4.68 (d, J=5.8 Hz, 2H), 3.36-3.26 (m, 4H)

HPLCMS (Method A): [m/z]: 331.1 [M+H]⁺

2-(2-Aminoethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (194)

In a similar fashion using general procedure 2, 12M HCl (2 ml) andtert-butylN-(2-{5-chloro-4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(188) (260 mg, 0.66 mmol) in MeOH (10 ml) at room temperature gave thetitle compound (198 mg, 82%) as a dark yellow gum. The crude product wasused without further purification.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.80 (d, J=5.4 Hz, 1H), 8.64 (td,J=8.0, 1.3 Hz, 1H), 8.16 (d, J=8.1 Hz, 1H), 8.03 (t, J=6.7 Hz, 1H), 4.99(s, 2H), 3.60-3.39 (m, 4H)

2-(2-Aminoethyl)-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (195)

In a similar fashion using general procedure 2, 12M HCl (1.86 ml) andtert-butylN-(2-{5-chloro-4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(189) (278 mg, 0.65 mmol) in MeOH (10 ml) at 60° C. gave the crude titlecompound (296 mg) as a pale brown residue. Compound was taken to thenext step without further purification.

HPLCMS (Method A): [m/z]: 298 [M+H]⁺

2-(2-Aminoethyl)-5-chloro-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (196)

In a similar fashion using general procedure 2, 12M HCl (1.56 ml) andtert-butylN-(2-{5-chloro-4-[(pyrimidin-2-ylmethyl)carbamoyl]-1,3-thiazol-2-yl}ethyl)carbamate(190) (483 mg, 0.938 mmol) in MeOH (3 ml) at 40° C. gave the titlecompound (563 mg, 100%) as a beige solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.83 (d, J=5.0 Hz, 2H), 7.49 (t,J=5.0 Hz, 1H), 4.82 (s, 2H), 3.49 (t, J=6.2 Hz, 2H), 3.39 (t, J=6.2 Hz,2H)

HPLCMS (Method A): [m/z]: 297.9 [M+H]⁺

2-(2-Aminoethyl)-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (197)

In a similar fashion using general procedure 2, 12M HCl (1.74 ml) andtert-butylN-[2-(5-chloro-4-{[(5-methylpyrimidin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(191) (580 mg, 1.04 mmol) in MeOH (6 ml) at room temperature gave thetitle compound (447 mg, 100%) as a white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.74 (s, 2H), 4.80 (s, 2H), 3.49(t, J=6.2 Hz, 2H), 3.38 (t, J=6.2 Hz, 2H), 2.39 (s, 3H)

HPLCMS (Method A): [m/z]: 311.95 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide (Example Compound No. 151)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (192) (143 mg, 0.37 mmol),1H-1,3-benzodiazole-2-carbaldehyde (70.1 mg, 0.48 mmol), MgSO₄ (200 mg)in MeOH (10 ml) at room temperature for 3 d, followed by addition ofNaBH₄ (28 mg, 0.74 mmol) gave the title compound (94 mg, 56%) as a whitesolid after purification by prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.19 (s, 1H), 8.71 (t, J=5.6 Hz, 1H),8.37 (dt, J=4.6, 1.3 Hz, 1H), 7.70 (ddd, J=10.0, 8.4, 1.1 Hz, 1H), 7.54(d, J=7.2 Hz, 1H), 7.45 (d, J=7.0 Hz, 1H), 7.40 (dt, J=8.6, 4.4 Hz, 1H),7.14 (t, J=7.5 Hz, 2H), 4.66-4.58 (m, 2H), 3.97 (s, 2H), 3.12 (t, J=6.3Hz, 2H), 2.94 (t, J=6.3 Hz, 2H)

HPLCMS (Method A): [m/z]: 445.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 159)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-5-chloro-N-[(3-chloropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (193) (320 mg, 0.79 mmol),1H-1,3-benzodiazole-2-carbaldehyde (127.3 mg, 0.87 mmol), DIPEA (0.32ml, 2.0 mmol) and MgSO₄ (300 mg) in MeOH (20 ml) at room temperature for16 h, followed by addition of NaBH₄ (60 mg, 1.59 mmol) gave the titlecompound (191 mg, 52%) as a white solid after purification by prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 8.72 (t, J=5.6 Hz, 1H),8.49 (dd, J=4.7, 1.3 Hz, 1H), 7.95 (dd, J=8.1, 1.3 Hz, 1H), 7.54 (s,1H), 7.46 (s, 1H), 7.38 (dd, J=8.1, 4.7 Hz, 1H), 7.17-7.09 (m, 2H), 4.65(d, J=5.5 Hz, 2H), 3.98 (d, J=4.1 Hz, 2H), 3.13 (t, J=6.3 Hz, 2H), 2.95(q, J=6.1, 5.3 Hz, 2H), 2.74 (s, 1H)

HPLCMS (Method C): [m/z]: 461 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 160)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (194) (190 mg, 0.51 mmol),1H-1,3-benzodiazole-2-carbaldehyde (113 mg, 0.77 mmol), DIPEA (0.3 ml,2.0 mmol) and MgSO₄ (400 mg) in DCM (10 ml) and MeOH (10 ml) at roomtemperature for 16 h, followed by addition of NaBH₄ (39 mg, 1.03 mmol)gave the title compound (60 mg, 27%) as a pale yellow solid afterpurification by prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.19 (s, 1H), 8.90 (t, J=6.0 Hz, 1H),8.50 (d, J=5.5 Hz, 1H), 7.75 (td, J=7.7, 1.8 Hz, 1H), 7.58-7.42 (m, 2H),7.31 (d, J=7.8 Hz, 1H), 7.27 (dd, J=7.0, 5.3 Hz, 1H), 7.17-7.10 (m, 2H),4.54 (d, J=6.0 Hz, 2H), 3.98 (s, 2H), 3.12 (t, J=6.3 Hz, 2H), 2.95 (t,J=6.3 Hz, 2H), 2.76 (s, 1H)

HPLCMS (Method C): [m/z]: 427.1 [M+H]⁺

5-chloro-N-(pyridin-2-ylmethyl)-2-(2-{1,8,12-triazatricyclo[7.4.0.0²,7]trideca-2(7),3,5,8-tetraen-12-yl}ethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 189)

In a similar fashion to general procedure 8,2-(2-Aminoethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (194) (361.5 mg, 0.98 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (187.9 mg, 0.98 mmol), DBU (219 μl,1.47 mmol) in MeCN (5 ml) at room temperature for 3 h, gave a mixture ofmono and bis alkylated intermediates which were separated by flashcolumn chromatography (eluting with a gradient of 0-10% MeOH/EtOAcfollowed by 0-10% MeOH/DCM). The mono alkylated intermediate(5-chloro-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide)(66.0 mg, 0.135 mmol) was further reacted with iron powder (15.1 mg,0.270 mmol) in AcOH (1 ml) at 80° C. for 1 h to give the title compound(61 mg, 25%) as a brown oil after purification by flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM).

¹H NMR (Acetone-d6, 500 MHz): d[ppm]=8.53 (d, J=4.2 Hz, 2H), 7.76 (td,J=7.7, 1.8 Hz, 1H), 7.61-7.53 (m, 1H), 7.45-7.37 (m, 2H), 7.26 (dd,J=7.0, 4.9 Hz, 1H), 7.22-7.14 (m, 2H), 5.14 (s, 2H), 4.66 (d, J=5.7 Hz,2H), 3.39 (t, J=6.2 Hz, 2H), 3.36-3.28 (m, 2H), 3.20 (t, J=6.3 Hz, 2H),3.14 (t, J=6.2 Hz, 2H)

HPLCMS (Method B): [m/z]: 453.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 161)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (195) (296 mg, 0.8 mmol),1H-1,3-benzodiazole-2-carbaldehyde (151.7 mg, 1.04 mmol), DIPEA (0.42ml, 2.0 mmol) and MgSO₄ (400 mg) in DCM (10 ml) and MeOH (10 ml) at roomtemperature for 3 d, followed by addition of NaBH₄ (60 mg, 1.59 mmol)gave the title compound (96 mg, 28%) as a white solid after purificationby prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.18 (s, 1H), 9.14 (dd, J=4.8, 1.5Hz, 1H), 9.07 (t, J=6.1 Hz, 1H), 7.66 (dd, J=8.5, 4.8 Hz, 1H), 7.60 (dd,J=8.5, 1.6 Hz, 1H), 7.54 (d, J=7.4 Hz, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.13(p, J=7.0, 6.6 Hz, 2H), 4.72 (d, J=6.1 Hz, 2H), 3.97 (s, 2H), 3.12 (t,J=6.3 Hz, 2H), 2.95 (t, J=6.2 Hz, 2H), 2.75 (s, 1H)

HPLCMS (Method C): [m/z]: 428 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 175)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-5-chloro-N-(pyrimidin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (196) (563 mg, 0.94 mmol),1H-benzimidazole-2-carbaldehyde (178 mg, 1.22 mmol), DIPEA (0.654 ml,0.74 mmol) in MeOH (15 ml) at room temperature for 24 h, followed byaddition of NaBH₄ (53 mg, 1.41 mmol) gave the title compound (224 mg,54%) as a white solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.20 (br s, 1H), 8.80-8.74 (m, 3H),7.50 (br s, 2H), 7.40 (t, J=4.9 Hz, 1H), 7.21-7.07 (m, 2H), 4.64 (d,J=5.9 Hz, 2H), 3.98 (s, 2H), 3.13 (t, J=6.3 Hz, 2H), 2.96 (t, J=6.3 Hz,2H), 2.76 (br s, 1H)

HPLCMS (Method G): [m/z]: 428.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 178)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (197) (223 mg, 0.52 mmol),1H-benzimidazole-2-carbaldehyde (99 mg, 0.68 mmol), DIPEA (0.363 ml,2.09 mmol) and MgSO₄ (400 mg) in MeOH (6 ml) at room temperature for 24h, followed by addition of NaBH₄ (30 mg, 0.78 mmol) gave the titlecompound (120 mg, 52%) as a white solid after purification by basicprep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.21 (s, 1H), 8.72 (t, J=5.8 Hz, 1H),8.63-8.57 (m, 2H), 7.50 (s, 1H), 7.14 (dd, J=6.0, 2.7 Hz, 2H), 4.61-4.56(m, 2H), 3.98 (s, 2H), 3.13 (t, J=6.3 Hz, 2H), 2.95 (t, J=6.3 Hz, 2H),2.75 (s, 1H), 2.26 (s, 3H)

HPLCMS (Method C): [m/z]: 442 [M+H]⁺

5-Chloro-N-[(3-fluoropyridin-2-yl)methyl]-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxamid(198)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(192) (700 mg, 2.22 mmol) and N-(2-nitrophenyl)prop-2-enamide (D) (470mg, 2.45 mmol) were combined in MeCN (40 ml) and DBU (0.37 ml, 2.0 mmol)was added. The mixture was stirred at room temperature for 3 d. Thereaction mixture was evaporated directly onto silica. Purification byflash column chromatography (eluting with a gradient of 0-10% MeOH/DCM)gave the title compound (390 mg, 25%) as a yellow solid.

HPLCMS (Method A): [m/z]: 507 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 154)

In a similar fashion to general procedure 8,5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-thiazole-4-carboxamide(198) (390 mg, 0.77 mmol) and iron powder (172 mg, 3 mmol) in AcOH (5ml) at 90° C. for 30 min gave the crude product. The residue was flushedthrough a plug of silica, gradient elution 0.5-40% MeOH/DCM then 20% 7 MNH₃ in MeOH/DCM, followed by further purification by basic prep-HPLC togive the required product as the free base. The residue was re-dissolvedin MeOH (10 ml) and treated with 12 M HCl (1 ml) for 1 h. The solventwas rigorously removed under vacuum to give the target compound as apale yellow solid.

1H-NMR (D₂O, 500 MHz): d[ppm]=8.33-8.30 (m, 1H), 7.87 (ddd, J=9.6, 8.6,1.2 Hz, 1H), 7.71 (dt, J=6.8, 3.4 Hz, 2H), 7.59 (dt, J=7.5, 4.2 Hz, 1H),7.55 (dt, J=6.3, 3.4 Hz, 2H), 3.72-3.62 (m, 6H), 3.44 (t, J=6.6 Hz, 2H).Note that a benzylic CH₂ signal is obscured by D20

HPLCMS (Method A): [m/z]: 459.1 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 182)

In a similar fashion using general procedure 8,2-(2-aminoethyl)-5-chloro-N-[(5-methylpyrimidin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (197) (0.223 g, 0.522 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (0.090 g, 0.47 mmol) and DBU (0.171ml, 1.148 mmol) in MeCN (10 ml) gave the intermediate (355 mg, 0.46mmol) which was further reacted with iron powder (104 mg, 1.86 mmol) inAcOH (5 ml) at 80° C. for 2.5 h gave the title compound (6 mg, 3%) as anoff-white solid after purification by basic prep-HPLC followed by flashcolumn chromatography (eluting with a gradient of 0-5% MeOH/DCM).

1H-NMR (DMSO-d4, 500 MHz): d[ppm]=8.54 (s, 2H), 7.47-7.41 (m, 2H),7.20-7.14 (m, 2H), 4.62 (s, 2H), 3.23-3.16 (m, 4H), 3.15-3.10 (m, 4H),2.28 (s, 3H)

HPLCMS (Method D): [m/z]: 456.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 183)

In a similar fashion using general procedure 8,2-(2-aminoethyl)-5-chloro-N-(pyridazin-3-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (195) (255 mg, 0.689 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (132 mg, 0.689) and DBU (0.154 ml,1.03 mmol) in MeCN (5 ml) gave the intermediate (112 mg, 0.16 mmol)which was further reacted with iron powder (18 mg, 0.33 mmol) in AcOH (1ml) at 80° C. for 2.5 h gave the title compound (6.4 mg, 8.5%) as ayellow oil after purification by flash column chromatography (elutingwith a gradient of 0-20% MeOH/DCM) followed by basic prep HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=9.08 (dd, J=4.3, 2.3 Hz, 1H),7.72-7.63 (m, 2H), 7.47 (dd, J=5.9, 3.2 Hz, 2H), 7.23-7.15 (m, 2H), 4.80(s, 2H), 3.16-3.02 (m, 8H)

HPLCMS (Method B): [m/z]: 440.4 [M−H]⁻

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 184)

In a similar fashion using general procedure 8,2-(2-aminoethyl)-5-chloro-N-(pyridin-2-ylmethyl)-1,3-thiazole-4-carboxamidedihydrochloride (194) (361.6 mg, 0.978 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (187.9 mg, 0.978 mmol), DBU (0.219ml, 1.467 mmol) in MeCN (5 ml) gave the intermediate (180 mg, 0.26 mmol)which was further reacted with iron powder (29 mg, 0.54 mmol) in AcOH (1ml) at 80° C. for 2 h gave the title compound (8.8 mg, 7.5%) as a yellowoil after purification by basic prep HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.47 (ddd, J=5.0, 1.6, 0.9 Hz,1H), 7.77 (td, J=7.7, 1.8 Hz, 1H), 7.47 (dd, J=5.9, 3.2 Hz, 2H), 7.37(d, J=7.9 Hz, 1H), 7.33-7.25 (m, 1H), 7.20-7.16 (m, 2H), 4.61 (s, 2H),3.16-3.01 (m, 8H)

HPLCMS (Method B): [m/z]: 439.3 [M−H]⁻

Ethyl5-bromo-2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate(199)

Ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate (1)(1.56 g, 5.19 mmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (1.86 g,10.0 mmol) were dissolved in THF (60 ml) and cooled to −78° C. 2 MNaHMDS (5.45 ml) was added dropwise and the mixture stirred at −78° C.for 2 h. The reaction was quenched with sat. NH₄Cl (aq) (30 ml) andallowed to warm to room temperature. The mixture was extracted with DCM(3×100 ml) and the combined organic extracts dried (Na₂SO₄), filteredand evaporated in vacuo. Purification by flash column chromatographyusing a gradient elution 10-50% EtOAc/heptane gave the title compound(1.62 g, 80%) as a colourless oil.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=4.91 (s, 1H), 4.46 (q, J=7.1 Hz, 2H),3.56 (q, J=6.3 Hz, 2H), 3.21 (t, J=6.3 Hz, 2H), 1.50-1.42 (m, 12H)

HPLCMS (Method A): [m/z]: 400.9/402.85 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxylate(200)

Ethyl5-bromo-2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate(199) (626 mg, 1.65 mmol), PdCl₂(dppf) (120 mg, 0.17 mmol) and K₂CO₃(460 mg, 3.0 mmol) were dissolved in MeCN (18 ml) and water (18 ml)under nitrogen and4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (0.38 ml,1.98 mmol) was added. The mixture was heated at 80° C. for 30 min,cooled to room temperature and diluted with water. The mixture wasextracted with DCM (3×80 ml) and the combined organic extracts dried(Na₂SO₄), filtered and evaporated in vacuo. Purification by flashchromatography using a gradient elution 10-60% EtOAc/heptane gave thetitle compound (558 mg, 99%) as a yellow oil.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.23 (s, 1H), 5.12 (s, 1H), 4.94 (s,1H), 4.32 (q, J=7.2 Hz, 2H), 3.47 (q, J=6.5 Hz, 2H), 3.09 (t, J=6.5 Hz,2H), 2.07 (s, 3H), 1.37 (s, 9H), 1.31 (t, J=7.2 Hz, 3H).

HPLCMS (Method A): [m/z]: 341.05 [M+H]⁺

Ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(trifluoromethyl)-1,3-thiazole-4-carboxylate(201)

Ethyl5-bromo-2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-thiazole-4-carboxylate(199) (0.54 g, 1.43 mmol) was dissolved in DMF (30 ml) under nitrogenand copper(I) iodide (1.36 g, 7.0 mmol), triphenylarsane (0.14 ml, 0.57mmol), Pd₂dba₃ (0.065 g, 0.07 mmol) and methyldifluoro(fluorosulfonyl)acetate (0.23 ml, 1.85 mmol) were added. Themixture was heated at 100° C. for 3 h, then cooled to room temperatureand concentrated in vacuo. The residue was partitioned between EtOAc andsat. NaHCO₃ (aq). The phases were separated and the aqueous phase wasextracted with EtOAc (2×80 ml) and the combined organic extracts werewashed with brine (2×50 ml), dried (Na₂SO₄), filtered and evaporated invacuo. Purification by flash column chromatography (eluting with agradient of 10-60% EtOAc/heptane) afforded the title compound (0.447 g,84%) as a yellow oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=4.92 (s, 1H), 4.48 (q, J=7.1 Hz, 2H),3.60 (q, J=6.2 Hz, 2H), 3.27 (t, J=6.2 Hz, 2H), 1.46 (s, 9H), 1.44 (t,J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 391 [M+Na]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxylicacid (202)

In a similar fashion to general procedure 5, ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxylate(200) (550 mg, 1.62 mmol) and LiOH (390 mg, 16.0 mmol) in THF (20 ml)and water (20 ml) gave the crude title compound (569 mg, quant.) as ayellow oil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=5.41 (s, 1H), 5.38 (s, 1H), 4.84 (s,1H), 3.59 (m, 2H), 3.16 (t, J=6.4 Hz, 2H), 2.23 (s, 3H), 1.47 (s, 9H)

HPLCMS (Method A): [m/z]: 312.9 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-5-(trifluoromethyl)-1,3-thiazole-4-carboxylicacid (203)

In a similar fashion to general procedure 5, ethyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(trifluoromethyl)-1,3-thiazole-4-carboxylate(201) (447 mg, 1.21 mmol) and LiOH (320 mg, 13.0 mmol) in THF (15 ml)and water (15 ml) afforded the title compound (365 mg, 88%) as a paleyellow solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=4.81 (s, 1H), 3.53 (q, J=6.0 Hz, 2H),3.18 (br s, 2H), 1.37 (s, 9H)

HPLCMS (Method A): [m/z]: 362.95 [M+Na]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-(prop-1-en-2-yl)-1,3-thiazol-2-yl)ethyl]carbamate(204)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxylicacid (202) (569 mg, 1.82 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (435 mg, 2.19 mmol), DIPEA (1.11 ml, 6.0 mmol) andHATU (830 mg, 2.0 mmol) in DCM (20 ml) gave the title compound (544 mg,71%) as a colourless oil after purification by flash columnchromatography (eluting with a gradient of 0-60% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.51-8.43 (m, 2H), 7.45-7.38 (m, 1H),7.30-7.24 (m, 1H), 5.34 (m, 1H), 5.27 (s, 1H), 4.83 (dd, J=5.1, 1.6 Hz,2H), 3.61 (m, 2H), 3.15 (m, 2H), 2.25 (s, 3H), 1.46 (s, 9H).

HPLCMS (Method A): [m/z]: 421.05 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-(trifluoromethyl)-1,3-thiazol-2-yl)ethyl]carbamate(205)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-(trifluoromethyl)-1,3-thiazole-4-carboxylicacid (203) (365 mg, 1.07 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (256.2 mg, 1.29 mmol), DIPEA (0.65 ml, 4 mmol) andHATU (490 mg, 1.3 mmol) in DCM (20 ml) gave the title compound (344 mg,72%) after purification by flash column chromatography (eluting with agradient of 20-30% EtOAc/heptane).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.49 (s, 1H), 8.35 (dt, J=4.6, 1.3 Hz,1H), 7.35 (ddd, J=9.4, 8.4, 1.3 Hz, 1H), 7.25-7.15 (m, 1H), 4.85 (s,1H), 4.77 (dd, J=5.0, 1.6 Hz, 2H), 3.54 (q, J=6.3 Hz, 2H), 3.17 (t,J=6.3 Hz, 2H), 1.37 (s, 9H)

HPLCMS (Method A): [m/z]: 449.05 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxamidedihydrochloride (206)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-(prop-1-en-2-yl)-1,3-thiazol-2-yl)ethyl]carbamate(204) (544 mg, 1.29 mmol) and 12 M HCl (2 ml) in MeOH (10 ml) gave thetitle compound (486 mg, 94%) as a white solid.

HPLCMS (Method A): [m/z]: 321 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(trifluoromethyl)-1,3-thiazole-4-carboxamidedihydrochloride (207)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-(trifluoromethyl)-1,3-thiazol-2-yl)ethyl]carbamate(205) (347 mg, 0.77 mmol) and 12 M HCl (2 ml) in MeOH (10 ml) gave thetitle compound (330 mg, quant.) as a white solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=9.22 (t, J=5.6 Hz, 1H), 8.40 (dt,J=4.6, 1.4 Hz, 1H), 8.16 (s, 3H), 7.74 (ddd, J=10.1, 8.4, 1.4 Hz, 1H),7.43 (dt, J=8.4, 4.4 Hz, 1H), 4.68 (dd, J=5.8, 1.5 Hz, 2H), 3.42-3.22(m, 4H)

HPLCMS (Method A): [m/z]: 349 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxamide (ExampleCompound No. 177)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxamidedihydrochloride (206) (260 mg, 0.66 mmol),1H-benzimidazole-2-carbaldehyde (96.6 mg, 0.66 mmol), DIPEA (0.36 ml,2.0 mmol) and MgSO₄ (300 mg) in MeOH (20 ml) at room temperature for 18h, followed by addition of NaBH₄ (500 mg, 1.3 mmol) afforded the titlecompound (148 mg, 50%) as pale yellow solid after purification by basicprep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.19 (s, 1H), 8.67 (t, J=5.5 Hz, 1H),8.36 (d, J=4.6 Hz, 1H), 7.69 (t, J=8.8 Hz, 1H), 7.58-7.43 (m, 2H), 7.40(m, 1H), 7.16-7.09 (m, 2H), 5.21 (s, 1H), 5.15 (s, 1H), 4.61 (d, J=5.5Hz, 2H), 3.97 (s, 2H), 3.11 (t, J=6.7 Hz, 2H), 2.96 (t, J=6.7 Hz, 2H),2.08 (s, 3H)

HPLCMS (Method C): [m/z]: 451.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide (ExampleCompound No. 176)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(trifluoromethyl)-1,3-thiazole-4-carboxamidedihydrochloride (207) (130 mg, 0.31 mmol),1H-benzimidazole-2-carbaldehyde (67.6 mg, 0.46 mmol), DIPEA (0.16 ml,0.93 mmol) and MgSO₄ (300 mg) in MeOH (10 ml) at room temperature for 16h, followed by addition of NaBH₄ (23 mg, 0.62 mmol) gave the titlecompound (81 mg, 55%) as pale yellow solid after purification by basicprep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.21 (s, 1H), 8.96 (t, J=5.7 Hz, 1H),8.37 (dt, J=4.6, 1.3 Hz, 1H), 7.71 (ddd, J=10.0, 8.3, 1.3 Hz, 1H), 7.53(s, 1H), 7.45 (s, 1H), 7.41 (dt, J=8.3, 4.4 Hz, 1H), 7.14 (s, 2H), 4.65(dd, J=5.7, 1.4 Hz, 2H), 3.99 (s, 2H), 3.22 (t, J=6.3 Hz, 2H), 2.99 (t,J=6.3 Hz, 2H), 2.80 (s, 1H)

HPLCMS (Method C): [m/z]: 479.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-(propan-2-yl)-1,3-thiazole-4-carboxamide (ExampleCompound No. 180)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-5-(prop-1-en-2-yl)-1,3-thiazole-4-carboxamide(Example Compound No. 177) (120 mg, 0.27 mmol), and palladium on carbon(10%, 28 mg, 0.027 mmol) were combined in EtOH (10 ml) and the mixturestirred under an atmosphere of hydrogen for 1.5 h. The reaction mixturewas filtered through a plug of Celite and the residue rinsed with MeOH.The combined filtrates were evaporated in vacuo and purified by basicprep-HPLC to afford the title compound (68 mg, 56%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.20 (s, 1H), 8.60 (t, J=5.6 Hz, 1H),8.38-8.34 (m, 1H), 7.70 (m, 1H), 7.58-7.43 (m, 2H), 7.40 (dt, J=8.6, 4.4Hz, 1H), 7.16-7.09 (m, 2H), 4.63 (dd, J=5.6, 1.4 Hz, 2H), 4.24 (hept,J=6.8 Hz, 1H), 3.96 (s, 2H), 3.11 (t, J=6.8 Hz, 2H), 2.95 (t, J=6.8 Hz,2H), 1.21 (d, J=6.8 Hz, 6H)

HPLCMS (Method C): [m/z]: 453.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(trifluoromethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 186)

In a similar fashion using general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-(trifluoromethyl)-1,3-thiazole-4-carboxamidedihydrochloride (207) (242 mg, 0.57 mmol),N-(2-nitrophenyl)prop-2-enamide (110.4 mg, 0.57 mmol) and DBU (0.301 ml,2 mmol) in MeCN (10 ml) gave a crude intermediate which was furtherreacted with iron powder (56 mg, 1 mmol) in AcOH (3 ml) to give thetitle compound (4 mg, 2%) after two purifications by basic prep-HPLC anda final purification by flash column chromatography (eluting with agradient of 0-20% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.94 (t, J=5.5 Hz, 1H),8.39 (dt, J=4.5, 1.4 Hz, 1H), 7.71 (ddd, J=9.9, 8.3, 1.4 Hz, 1H), 7.41(m, 2H), 7.10 (m, 2H), 4.64 (dd, J=5.7, 1.4 Hz, 2H), 3.18 (t, J=6.1 Hz,2H), 3.06 (t, J=6.1 Hz, 2H), 3.02-2.92 (m, 4H)

HPLCMS (Method C): [m/z]: 493.1 [M+H]⁺

2-(Ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid (216)

3-Bromo-2-oxopropanoic acid and ethyl amino(thioxo)acetate in THF (100ml) were stirred at 60° C. for 16 h. The reaction mixture was reduced invacuo to give an orange solid. The solid was triturated with Et₂O,filtered and dried in vacuo to give the titled compound (4.54 g, 62.8%)as a colourless solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=13.40 (s, 1H), 8.77 (s, 1H), 4.40 (q,J=7.1 Hz, 2H), 1.35 (t, J=7.1 Hz, 3H)

HPLCMS (ESI+): [m/z]: 201.90 [M+H]⁺

Ethyl 4-(hydroxymethyl)-1,3-thiazole-2-carboxylate (217)

Isobutyl chloroformate (1.16 ml, 8.95 mmol) was added to an ice-cooled(0° C.) suspension of 2-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid(216) (1.5 g, 7.46 mmol) and TEA (1.25 ml, 8.95 mmol) in THF (60 ml).The reaction was stirred at 0° C. for 1 h. The reaction was filteredthrough a plug of Celite and NaBH₄ (0.705 g, 18.64 mmol) was added tothe filtrate and stirred for 2 h. The reaction was diluted with sat. aq.Na₂CO₃ solution and stirred for 10 mins, then extracted with EtOAc. Thecombined organic layers were washed with brine, dried (Na₂SO₄), filteredand the solvent evaporated.

Purification by flash column chromatography (eluting with a gradient of40-50% EtOAc-Heptane) gave the titled compound (0.734 g, 52.6%) as acrystalline solid.

1H-NMR (DMSO-d6, 500 MHz) d[ppm]=7.85 (s, 1H), 5.50 (t, J=5.8 Hz, 1H),4.63 (dd, J=5.8, 0.8 Hz, 2H), 4.37 (q, J=7.1 Hz, 2H), 1.33 (d, J=7.1 Hz,3H)

HPLCMS (ESI+): [m/z]: 187.90 [M+H]⁺

Ethyl 4-{[(benzyloxy)methoxy]methyl}-1,3-thiazole-2-carboxylate (218)

NaH (60%, 0.106 g, 2.66 mmol) was added to an ice-cooled (00° C.)solution of ethyl 4-(hydroxymethyl)-1,3-thiazole-2-carboxylate (217)(0.415 g, 2.22 mmol) in THF (20 ml) and the reaction stirred at 0° C.for 30 mins. [(Chloromethoxy)methyl]benzene (0.416 g, 2.66 mmol) wasadded and the reaction allowed to warm to room temperature over 3 h. Thereaction was quenched by addition of sat. aq. NH₄Cl and extracted withEtOAc. The combined organic layers were combined, washed with brine,dried (Na₂SO₄), filtered and the solvent evaporated. Purification byflash column chromatography (eluting with 30-50% EtOAc-Heptane) gave thetitle compound (0.392 g, 48.9%) as a colourless oil.

1H-NMR (CDCl₃, 500 MHz) d[ppm]=7.52-7.50 (m, 1H), 7.36-7.33 (m, 5H),4.90 (s, 2H), 4.86 (d, J=0.8 Hz, 2H), 4.66 (s, 2H), 4.48 (q, J=7.1 Hz,2H), 1.44 (t, J=7.1, 3H).

HPLCMS (ESI+): [m/z]: 307.95 [M+H]⁺

4-{[(Benzyloxy)methoxy]methyl}-1,3-thiazole-2-carboxylic acid (219)

In a similar fashion to general procedure 5, LiOH (64 mg, 1.53 mmol) wasadded to a solution of ethyl4-{[(benzyloxy)methoxy]methyl}-1,3-thiazole-2-carboxylate (218) (85%,0.39 g, 1.28 mmol) in THF (5 ml), MeOH (5 ml) and water (5 ml) at roomtemperature for 4 h, gave the title compound (0.35 g, 88.4%) as acolourless oil.

1H-NMR (DMSO-d6, 500 MHz) d[ppm]=7.95 (s, 1H), 7.36-7.33 (m, 5H), 4.84(s, 2H), 4.74 (s, 2H), 4.60 (s, 2H), 4.49 (s, 1H).

HPLCMS (ESI+): [m/z]: 279.95 [M+H]⁺

4-{[(Benzyloxy)methoxy]methyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-2-carboxamide(220)

In a similar fashion to general procedure 6,4-{[(benzyloxy)methoxy]methyl}-1,3-thiazole-2-carboxylic acid (219)(0.350 g, 1.25 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride(A2) (0.374 g, 1.88 mmol), DIPEA (0.89 ml, 5.01 mmol) and HATU (0.714 g,1.88 mmol) in DMF (10 ml) at room temperature for 16 h, gave the titlecompound (0.381 g, 76.1%) as a yellow oil after purification by flashcolumn chromatography (eluting with a gradient of 0-5% MeOH-DCM).

1H-NMR (CDCl₃, 250 MHz) d[ppm]=8.42-8.38 (m, 1H), 7.40-7.27 (m, 7H),4.90 (s, 2H), 4.86-4.82 (m, 2H), 4.80 (d, J=0.6 Hz, 2H), 4.68 (s, 2H)

HPLCMS (ESI+): [m/z]: 388.05 [M+H]⁺

N-[(3-Fluoropyridin-2-yl)methyl]-4-(hydroxymethyl)-1,3-thiazole-2-carboxamide(221)

TFA (1 ml, 13.06 mmol) was added to an ice-cooled (00) solution of4-{[(benzyloxy)methoxy]methyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-2-carboxamide(220) (0.185 g, 0.48 mmol) in DCM (4 ml). The reaction allowed to warmto room temperature and stirred for 16 h. The solvent evaporated and theresulting residue dissolved in EtOAc (5 ml) and washed with sat. aq.NaHCO₃ (20 ml), brine (10 ml), dried (Na₂SO₄), filtered and the solventevaporated. Purification by flash column chromatography (eluting with agradient of 5% MeOH-DCM) gave the titled compound (0.085 g, 73.2%) as acolourless powder.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.45-8.41 (m, 1H), 8.36 (br s, 1H), 7.45(s, 1H), 7.44-7.40 (m, 1H), 7.31-7.26 (m, 1H), 4.85 (dd, J=5.1, 1.6 Hz,2H), 4.83 (d, J=5.6 Hz, 2H), 2.20 (t, J=6.0 Hz, 1H)

HPLCMS (ESI+): [m/z]: 267.95 [M+H]⁺

N-[(3-Fluoropyridin-2-yl)methyl]-4-formyl-1,3-thiazole-2-carboxamide(222)

IBX (189 mg, 0.70 mmol) was added to a solution ofN-[(3-fluoropyridin-2-yl)methyl]-4-(hydroxymethyl)-1,3-thiazole-2-carboxamide(221) (60 mg, 0.22 mmol) in MeCN (5 ml) and the reaction heated at 80°C. for 3 h. The reaction was cooled to room temperature and filteredthrough Celite. The solution was directly absorbed onto silica andpurified by flash column chromatography (eluting with a gradient of 5%MeOH-DCM). The product was re-purified by flash column chromatography(eluting with a gradient of 30-50% EtOAc-Heptane) to give titledcompound (56 mg, 94%) as a colourless solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=10.10 (s, 1H), 8.46 (br s, 1H),8.46-8.44 (m, 1H), 8.37 (s, 1H), 7.46-7.42 (m, 1H), 7.33-7.28 (m, 1H),4.88 (dd, J=5.1, 1.7 Hz, 2H)

HPLCMS (ESI+): [m/z]: 265.95 [M+H]⁺

4-({[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-2-carboxamide(Example Compound No. 205)

A solution ofN-[(3-fluoropyridin-2-yl)methyl]-4-formyl-1,3-thiazole-2-carboxamide(222) (56 mg, 0.21 mmol) in DCE (1 mL) was added to a suspension of2-(1H-1,3-benzodiazol-2-yl)ethan-1-amine dihydrochloride (50 mg, 0.21mmol) and DIPEA (147 μl, 0.84 mmol) in DCE (2 ml). 4 Å activatedmolecular sieves were added and the solution stirred at room temperaturefor 2 h, then filtered and the filtrates concentrated in vacuo. Theresidue was dissolved in MeOH (10 ml) and cooled to 00. NaBH₄ (12 mg,0.32 mmol) was added, the mixture was warmed to room temperature andstirred for 1 h, then quenched with sat. Na₂CO₃(aq) and extracted withEtOAc (2×10 ml). The combined organic extracts were dried (Na₂SO₄),filtered and evaporated in vacuo. Purification by basic prep-HPLCafforded the title compound (44 mg, 51%) as a colourless foam.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.31 (dt, J=4.5, 1.2 Hz, 1H), 7.62(s, 1H), 7.57 (ddd, J=9.8, 8.5, 1.2 Hz, 1H), 7.46 (dt, J=6.6, 3.3 Hz,2H), 7.36 (dt, J=8.5, 4.5 Hz, 1H), 7.18-7.14 (m, 2H), 4.75 (d, J=1.6 Hz,2H), 3.96 (s, 2H), 3.13-3.07 (m, 4H).

HPLCMS (Method C): [m/z]: 411.1 [M+H]⁺

General Scheme 12 Above General Procedure 13: methyl2-(3-{[(tert-butoxy)carbonyl]amino}propanamido)-3-hydroxypropanoate(223)

TEA (8.38 ml, 60.1 mmol) was added to a cooled (00) solution of methylserinate hydrochloride (1:1) (8.5 g, 54.6 mmol) in DCM (250 ml) undernitrogen. N-(tert-butoxycarbonyl)-beta-alanine (10.3 g, 54.6 mmol) andDCC (12.4 g, 60.1 mmol) were added portionwise. The reaction mixture wasallowed to warm to room temperature and stirred for 19 h. The solventwas evaporated and EtOAc (250 ml) was added. The mixture was heated to50° C. and stirred for 20 min, cooled to room temperature and filtered.The filtrate was evaporated to give a waxy off-white solid (21.7 g). Thesolid was dissolved in MeOH (200 ml) and silica (300 ml volume) wasadded. The solvent was evaporated under reduced pressure to give thecompound dry loaded onto silica. Purification by flash columnchromatography (eluting with a gradient of 20% EtOAc/heptane (2 L), 40%EtOAc/heptane (4 L), 80% EtOAc/heptane (2 L) followed by EtOAc (8 L)gave the title compound (10.4 g, 64.4%) as an off-white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=6.62 (s, 1H), 5.12 (s, 1H), 4.65 (dt,J=7.1, 3.4 Hz, 1H), 3.96 (t, J=3.2 Hz, 2H), 3.80 (s, 3H), 3.55-3.33 (m,2H), 2.95 (s, 1H), 2.48 (td, J=5.8, 2.6 Hz, 2H), 1.43 (s, 9H)

HPLCMS (Method A): [m/z]: 291 [M+H]⁺

Methyl 2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)-3-hydroxypropanoate(224)

In a similar fashion to general procedure 13, methyl serinatehydrochloride (3 g, 19.28 mmol), TEA (2.96 ml, 21.21 mmol),N-(tert-butoxycarbonyl)glycine (3.38 g, 19.28 mmol) and DCC (4.38 g,21.21 mmol) in DCM (100 ml) afforded the title compound (4.5 g, 69%) asa pale yellow oil after purification by flash chromatography using anelution gradient 20-100% EtOAc/heptane.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.07 (d, J=7.4 Hz, 1H), 5.32 (s, 1H),4.77-4.60 (m, 1H), 3.99 (m, 2H), 3.87 (m, 2H), 3.81 (s, 3H), 3.04 (s,1H), 1.48 (s, 9H)

HPLCMS (Method A): [m/z]: 298.95 [M+Na]⁺

General Procedure 14: methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4,5-dihydro-1,3-oxazole-4-carboxylate(225)

Methyl2-(3-{[(tert-butoxy)carbonyl]amino}propanamido)-3-hydroxypropanoate(223) (98%, 10.42 g, 35.17 mmol) was dissolved in anhydrous DCM (280 ml)under nitrogen. The reaction mixture was cooled in a CO₂/MeCN bath(approx. −50° C.) and stirred for 30 min. DAST (5.58 ml, 42.21 mmol) wasadded dropwise and the mixture was stirred at −50° C. for 2.25 h. K₂COO₃(4.86 g, 35.17 mmol) was added in one portion and the reaction mixturewas allowed to stir for 20 min, before it was warmed up to roomtemperature. The reaction mixture was then immersed in a water bath andwater (60 ml) was added cautiously (effervescence occurred) to thereaction followed by 2 M NaOH (5 ml). The reaction mixture was stirredfor further 10 min and the layers were then separated. The aqueous layerwas extracted with DCM (2×50 ml). The combined organic layers were dried(MgSO4), filtered and evaporated to give the title compound (10.3 g) asan orange oil. The crude product was carried through the next stepwithout further purification.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=5.14 (s, 1H), 4.72 (ddt, J=10.3, 7.6,1.2 Hz, 1H), 4.47 (dd, J=8.7, 7.7 Hz, 1H), 4.39 (dd, J=10.6, 8.8 Hz,1H), 3.78 (s, 3H), 3.49-3.36 (m, 2H), 2.48 (td, J=6.2, 1.2 Hz, 2H), 1.42(s, 9H)

HPLCMS (Method A): [m/z]: 273 [M+H]⁺

Methyl2-({[(tert-butoxy)carbonyl]amino}methyl)-4,5-dihydro-1,3-oxazole-4-carboxylate(226)

In a similar fashion to general procedure 14, methyl2-(2-{[(tert-butoxy)carbonyl]amino}acetamido)-3-hydroxypropanoate (224)(2.5 g, 7.42 mmol) and DAST (1.18 ml, 8.9 mmol) in DCM (70 ml) affordedthe title compound (2.02 g, quant.) as a yellow oil.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.12 (s, 1H), 4.86-4.68 (m, 1H),4.62-4.42 (m, 2H), 4.11-3.89 (m, 2H), 3.82 (s, 3H), 1.44 (s, 9H)

HPLCMS (Method A): [m/z]: 258.95 [M+H]⁺

General Procedure 15: methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylate(227)

Bromo(trichloro)methane (10.4 ml, 105.56 mmol) was added to a solutionof methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4,5-dihydro-1,3-oxazole-4-carboxylate(225) (93.2%, 10.28 g, 35.19 mmol) in anhydrous DCM (300 ml) undernitrogen cooled to 0° C. DBU (15.75 ml, 105.56 mmol) was added dropwiseand the mixture was allowed to warm to room temperature and stirred for2.5 h. Saturated aqueous citric acid (25 ml) was added followed by water(100 ml). The reaction mixture was stirred vigorously for 10 min. Thelayers were separated and the aqueous layer was extracted with DCM(3×100 ml). The organic layer was dried (MgSO4), filtered and evaporatedto give a dark brown oil (14.6 g). The crude oil was dry loaded ontosilica with MeOH (200 ml). The crude material was filtered through asilica plug [gradient elution with heptane (2×500 ml), 25% EtOAc/heptane(2×500 ml) and 50% EtOAc/heptane (11×500 ml)] to give the title compound(8.63 g) as a yellow oil which solidified on standing.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.16 (s, 1H), 4.99 (s, 1H), 3.90 (s,3H), 3.57 (q, J=6.0 Hz, 2H), 2.99 (t, J=6.3 Hz, 2H), 1.40 (s, 9H)

HPLCMS (Method A): [m/z]: 293.0 [M+Na]⁺

Methyl2-({[(tert-butoxy)carbonyl]amino}methyl)-4,5-dihydro-1,3-oxazole-4-carboxylate(228)

In a similar fashion to general procedure 15, methyl2-({[(tert-butoxy)carbonyl]amino}methyl)-4,5-dihydro-1,3-oxazole-4-carboxylate(226) (2.02 g, 7.43 mmol), DBU (3.33 ml, 22.29 mmol) andbromo(trichloro)methane (2.2 ml, 22.29 mmol) in DCM (75 ml) afforded thetitle compound (1.04 g, 55%) as a colourless oil after purification byflash column chromatography using an elution gradient 0-100%TBME/heptane.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.19 (s, 1H), 5.19 (br. s, 1H), 4.49 (d,J=5.5 Hz, 2H), 3.92 (s, 3H), 1.45 (s, 9H)

HPLCMS (Method A): [m/z]: 278.95 [M+Na]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylic acid(229)

In a similar fashion using general procedure 5, LiOH (1.02 g, 42.76mmol) and methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylate(227) (97%, 6.62 g, 23.76 mmol) in THF (100 ml), and water (25 ml) gavethe title compound (4.8 g, 79%) as an off white powder.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.62 (s, 1H), 6.94 (t, J=5.4 Hz, 1H),3.31-3.26 (m, 2H, partially obscured by HOD peak), 2.87 (t, J=6.8 Hz,2H), 1.35 (s, 9H)

HPLCMS (Method A): [m/z]: 278.9 [M+Na]⁺

2-({[(Tert-butoxy)carbonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid(230)

In a similar fashion to general procedure 5, methyl2-({[(tert-butoxy)carbonyl]amino}methyl)-4,5-dihydro-1,3-oxazole-4-carboxylate(228) (1.04 g, 4.06 mmol) and LiOH (0.15 g, 6.09 mmol) in THF/water (20ml/5 ml) afforded the title compound (1.07 g, quant.) as an off-whitesolid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.29 (s, 1H), 5.39 (br. s, 1H), 4.54 (d,J=4.9 Hz, 2H), 1.47 (s, 9H)

HPLCMS (Method A): [m/z]: 265 [M+Na]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate(231)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylic acid(229) (3.78 g, 14.75 mmol), HATU (6.17 g, 16.23 mmol), (DIPEA) (8.48 ml,48.68 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride (A2)(2.94 g, 14.75 mmol) in THF/water (100 ml/40 ml) gave the title compound(4.83 g, 87%) as a yellow glassy solid after purification by flashcolumn chromatography (eluting with a gradient 0-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.51 (s, 2H), 8.40 (d, J=4.4 Hz, 1H),7.70 (t, J=9.3 Hz, 1H), 7.45-7.37 (m, 1H), 6.98 (t, J=5.5 Hz, 1H), 4.62(d, J=5.5 Hz, 2H), 3.32-3.28 (m, 2H, signal partially obscured by HODpeak), 2.90 (t, J=6.7 Hz, 2H), 1.35 (s, 9H)

HPLCMS (Method A): [m/z]: 365.0 [M+H]⁺

Tert-butylN-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}ethyl)carbamate(232)

In a similar fashion using general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylic acid(229) (4 g, 15.61 mmol), DIPEA (5.44 ml, 31.22 mmol), HATU (8.9 g, 23.41mmol), pyridin-2-ylmethanamine (2.41 ml, 23.41 mmol) in DMF (65 ml) gavethe title compound (6.03 g) as a yellow viscous oil after purificationby flash column chromatography (eluting with a gradient 0-100%EtOAc/heptane).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.74 (t, J=5.9 Hz, 1H), 8.54-8.48 (m,2H), 7.75 (td, J=7.7, 1.8 Hz, 1H), 7.32-7.22 (m, 2H), 6.98 (s, 1H), 4.52(d, J=6.0 Hz, 2H), 3.29 (d, J=6.5 Hz, 2H), 2.90 (t, J=6.7 Hz, 2H), 1.34(s, 9H)

HPLCMS (Method A): [m/z]: 347.1 [M+H]⁺

Tert-butylN-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate(233)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1,3-oxazole-4-carboxylic acid(229) (295 mg, 0.76 mmol, 66%), (3-chloropyridin-2-yl)methanaminedihydrochloride (246 mg, 1.14 mmol), TEA (0.1 ml, 0.76 mmol) and HATU(0.43 g, 1.14 mmol) in DMF (10 ml) afforded the title compound (202 mg,59%, 85% purity) as a yellow oil after purification by flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.58-8.45 (m, 2H), 7.96 (dd, J=8.1,1.4 Hz, 1H), 7.40 (dd, J=8.1, 4.7 Hz, 1H), 7.00 (t, J=6.2 Hz, 1H), 4.65(d, J=5.4 Hz, 2H), 2.97-2.86 (m, 4H), 1.35 (s, 9H)

HPLCMS (Method A): [m/z]: 381.05 [M+H]⁺

Tert-butylN-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)methyl]carbamate(234)

In a similar fashion to general procedure 6,2-({[(tert-butoxy)carbonyl]amino}methyl)-1,3-oxazole-4-carboxylic acid(230) (0.5 g, 2.06 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.41 g, 2.06 mmol), DIPEA (1.19 ml, 6.81 mmol) andHATU (0.86 g, 2.27 mmol) in THF (15 ml) and DMF (6 ml) gave the titlecompound (0.744 g, 98%) as a colourless oil after purification by flashchromatography using an elution gradient 0-100% EtOAc/heptane.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.56 (s, 1H), 8.51 (t, J=5.2 Hz, 1H),8.38 (d, J=4.6 Hz, 1H), 7.73-7.65 (m, 1H), 7.55 (t, J=5.8 Hz, 1H),7.44-7.37 (m, 1H), 4.65-4.59 (m, 2H), 4.29 (d, J=5.9 Hz, 2H), 1.39 (s,9H)

HPLCMS (Method A): [m/z]: 351.0 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235)

In a similar fashion using general procedure 2, tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate(231) (4.83 g, 12.86 mmol), 4 M HCl in 1,4-dioxane (50 ml) and DCM (80ml) gave the title compound (4.61 g) as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.71 (t, J=5.8 Hz, 1H), 8.59 (s, 1H),8.42-8.36 (m, 1H), 8.13 (br. s, 3H), 7.76-7.68 (m, 1H), 7.46-7.39 (m,1H), 4.64 (dd, J=5.8, 1.4 Hz, 2H), 3.25 (app. q, J=6.1 Hz, 2H),3.20-3.14 (m, 2H)

HPLCMS (Method F): [m/z]: 265.1 [M+H]⁺

2-(2-Aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamidedihydrochloride (236)

In a similar fashion using general procedure 2, tert-butylN-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}ethyl)carbamate(232) (90%, 6.03 g, 15.68 mmol), 12 M HCl (26.13 ml) in MeOH gave thetitle compound (5.78 g) as a cream foam.

1H-NMR (Methanol-d4, 250 MHz): d[ppm]=8.80 (dd, J=5.9, 0.8 Hz, 1H), 8.62(td, J=8.0, 1.6 Hz, 1H), 8.44 (s, 1H), 8.10 (d, J=7.8 Hz, 1H), 8.01 (t,J=6.3 Hz, 1H), 4.93 (s, 2H), 3.51-3.43 (m, 2H), 3.26 (t, J=6.4 Hz, 2H).

HPLCMS (Method A): [m/z]: 246.9 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (237)

In a similar fashion using general procedure 2, tert-butylN-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)ethyl]carbamate(233) (85%, 202 mg, 0.45 mmol), MeOH (5 ml) and 4 M HCl in dioxane (1.65ml) gave the title compound (125 mg, 62%) as a brown solid.

¹H NMR (DMSO-d6, 500 MHz): d[ppm]=8.67 (t, J=5.6 Hz, 1H), 8.61 (s, 1H),8.52 (dd, J=4.7, 1.4 Hz, 1H), 8.15 (s, 3H), 7.96 (dd, J=8.1, 1.4 Hz,1H), 7.40 (dd, J=8.1, 4.7 Hz, 1H), 4.67 (d, J=5.6 Hz, 2H), 3.29-3.23 (m,2H), 3.21-3.16 (m, 2H).

HPLCMS (Method A): [m/z]: 281.1 [M+H]⁺

2-(Aminomethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (238)

In a similar fashion to general procedure 2, tert-butylN-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)methyl]carbamate(234) (744 mg, 2.02 mmol) and 4 M HCl in 1,4-dioxane (15 ml) in DCM (20ml) afforded the title compound (668 mg, quant.) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.79 (s, 1H), 8.73 (br. s, 3H), 8.54(t, J=5.6 Hz, 1H), 8.39 (d, J=4.7 Hz, 1H), 7.80-7.68 (m, 1H), 7.49-7.38(m, 1H), 4.66 (d, J=4.6 Hz, 2H), 4.32 (t, J=5.5 Hz, 2H)

HPLCMS (Method F): [m/z]: 251.1 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidetrihydrochloride (Example Compound No. 127)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (1 g, 2.97 mmol), N-(2-nitrophenyl)prop-2-enamide(D) (0.63 g, 3.26 mmol) and DBU (1.5 ml, 10.08 mmol) in MeCN (30 ml) atroom temperature overnight gave the crude intermediate which was furtherreacted with iron powder (0.5 g) in AcOH (10 ml) under nitrogen at 80°C. for 3 h. the crude material was purified by basic prep-HPLC followedby further purification by flash column chromatography (eluting withgradient 0-30% MeOH in DCM) gave2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide.The free base was dissolved in MeOH (10 ml) and treated with 12 Mhydrogen chloride (1.5 ml). The solvent was then rigorously evaporatedunder vacuum to give the title compound (333 mg, 22%) as a white solid.

1H-NMR (D₂O, 500 MHz): d[ppm]=8.34-8.30 (m, 2H), 7.86 (ddd, J=9.6, 8.7,1.2 Hz, 1H), 7.74-7.69 (m, 2H), 7.62-7.57 (m, 1H), 7.57-7.52 (m, 2H),3.74-3.66 (m, J=4.3 Hz, 4H), 3.64 (t, J=6.7 Hz, 2H), 3.33 (t, J=6.7 Hz,2H)

HPLCMS (Method C): [m/z]: 409.1 [M+H]⁺

2-(2-{bis[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidetetrahydrochloride (Example Compound No. 128)

In a similar fashion to general procedure 7,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (Example Compound No. 127) (305 mg, 0.9 mmol),2-(2-chloroethyl)-1H-1,3-benzodiazole hydrochloride (216 mg, 1 mmol) andDIPEA (3.15 ml, 18 mmol) in DMF (5 ml) afforded the title compoundfreebase after purification by basic prep-HPLC. The freebase was treatedwith 12 M HCl (0.5 ml) in MeOH (5 ml) to afford the title compound astetrahydrochloride sal (5 mg, 0.8%) as a brown residue.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.56-8.52 (m, 1H), 8.45 (s, 1H),8.21-8.15 (m, 1H), 7.90-7.84 (m, 2H), 7.84-7.77 (m, 3H), 7.69-7.60 (m,3H), 7.58 (ddd, J=8.2, 7.4, 0.6 Hz, 1H), 5.32-5.22 (m, 2H), 4.90 (s,2H), 4.17-4.11 (m, 2H), 4.02-3.94 (m, 2H), 3.93-3.86 (m, 2H), 3.78 (t,J=6.3 Hz, 2H), 3.48 (t, J=6.3 Hz, 2H)

HPLCMS (Method C): [m/z]: 553.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamidetrihydrochloride (Example Compound No. 171)

In a similar fashion using general procedure 8,2-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamidedihydrochloride (236) (86%, 1.2 g, 3.25 mmol), DBU (1.46 ml, 9.76 mmol)and N-(2-nitrophenyl)prop-2-enamide (D) (0.69 g, 3.58 mmol) in MeCN (30ml) gave the crude intermediate, which was further reacted with ironpowder (0.52 g) in AcOH (10 ml) to give the title compound (0.22 g, 12%)as a pale brown solid.

1H-NMR (D₂O), 500 MHz): d[ppm]=8.72 (d, J=5.8 Hz, 1H), 8.54 (td, J=8.0,1.5 Hz, 1H), 8.46 (s, 1H), 8.00-7.94 (m, 2H), 7.81 (dt, J=6.2, 3.2 Hz,2H), 7.63 (dt, J=6.2, 3.3 Hz, 2H), 4.88 (s, 2H), 3.83-3.70 (m, 6H), 3.43(t, J=6.9 Hz, 2H)

HPLCMS (Method C): [m/z]: 391.2 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 173)

In a similar fashion using general procedure 8,2-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (237) (75%, 120 mg, 0.25 mmol), DBU (76 μl, 0.51 mmol)and N-(2-nitrophenyl)prop-2-enamide (D) (48 mg, 0.25 mmol) in MeCN (5ml) gave the crude intermediate, which was further reacted with ironpowder (36.9 mg) in AcOH (2 ml) to give the title compound (4.6 mg, 3%)as a clear film after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.44 (dd, J=4.7, 1.4 Hz, 1H), 8.28(s, 1H), 7.86 (dd, J=8.1, 1.4 Hz, 1H), 7.47-7.41 (m, 2H), 7.33 (dd,J=8.1, 4.8 Hz, 1H), 7.19-7.14 (m, 2H), 4.70 (s, 2H), 3.18-3.04 (m, 8H)

HPLCMS (Method C): [m/z]: 425.2 [M+H]⁺

2-({[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 206)

In a similar fashion to general procedure 8,2-(aminomethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (238) (300 mg, 0.93 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (196 mg, 1.02 mmol) and DBU (471.1μl, 3.16 mmol) in MeCN (10 ml) gave a crude intermediate which wasfurther reacted with iron powder (156 mg, 2.79 mmol) in AcOH (5 ml) toafford the title compound (20 mg, 27%) as a white solid afterpurification by basic prep-HPLC followed by flash chromatography usingan elution gradient 2-20% MeOH/DCM.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.57 (s, 1H), 8.53 (t,J=5.6 Hz, 1H), 8.38 (dt, J=4.6, 1.3 Hz, 1H), 7.70 (m, 1H), 7.51 (d,J=6.9 Hz, 1H), 7.41 (m, 2H), 7.15-7.07 (m, 2H), 4.62 (dd, J=5.6, 1.3 Hz,2H), 3.92 (s, 2H), 3.04-2.99 (m, 2H), 2.98-2.94 (m, 2H)

HPLCMS (Method C): [m/z]: 395.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide trihydrochloride (ExampleCompound No. 126)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (100 mg, 0.3 mmol),1H-benzimidazole-2-carbaldehyde (43.3 mg, 0.3 mmol), DIPEA (0.207 ml,1.19 mmol) and anhydrous MgSO₄ (200 mg) in DCM (10 ml) at roomtemperature for 16 h, followed by addition of NaBH₄ (17 mg, 0.45 mmol)afforded the free base compound after purification by basic prep-HPLC.The residue was re-dissolved in MeOH (5 ml) and treated with 12M HCl (1ml) for 30 min to give the title compound (64 mg, 42%) as a whitehygroscopic solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.57 (dd, J=5.4, 0.9 Hz, 1H), 8.46(s, 1H), 8.26-8.19 (m, 1H), 7.88 (ddt, J=13.4, 8.9, 4.1 Hz, 3H), 7.68(td, J=6.3, 5.5, 2.1 Hz, 2H), 5.02 (s, 2H), 4.94 (s, 2H), 3.83 (t, J=6.3Hz, 2H), 3.47 (t, J=6.3 Hz, 2H)

HPLCMS (Method C): [m/z]: 395.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridine-2-ylmethyl)-1,3-oxazole-4-carboxamide(Example Compound No. 137)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-(pyridine-2-ylmethyl)-1,3-oxazole-4-carboxamidedihydrochloride (236) (430 mg, 1.31 mmol),1H-benzimidazole-2-carbaldehyde (229 mg, 1.57 mmol) and DIPEA (0.91 ml,5.23 mmol) in MeOH (20 ml) at room temperature for 17 h, followed byaddition of NaBH₄ (74 mg, 1.96 mmol) afforded the title compound (380mg, 77%) as a yellow solid after purification by flash chromatographyusing a gradient elution of 0-20% MeOH/DCM.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.72 (t, J=5.9 Hz, 1H),8.53-8.46 (m, 2H), 7.74 (td, J=7.7, 1.7 Hz, 1H), 7.48 (m, 2H), 7.31-7.22(m, 2H), 7.12 (m, 2H), 4.52 (d, J=6.0 Hz, 2H), 3.95 (s, 2H), 3.03-2.93(m, 4H)

HPLCMS (Method C): [m/z]: 377.2 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 141)

In a similar fashion using general procedure 3,2-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (237) (118 mg, 0.31 mmol),1H-benzimidazole-2-carbaldehyde (54 mg, 0.37 mmol) and DIPEA (0.216 ml,1.24 mmol) in MeOH (4 ml) at room temperature for 24 h, followed byaddition of NaBH₄ (18 mg, 0.46 mmol) gave the title compound (51 mg,40%) as a brown solid after purification by basic prep-HPLC.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.41 (dd, J=4.8, 1.4 Hz, 1H), 8.29(s, 1H), 7.86 (dd, J=8.1, 1.4 Hz, 1H), 7.53-7.49 (m, 2H), 7.34-7.30 (m,1H), 7.21-7.18 (m, 2H), 4.76 (s, 2H), 4.08 (s, 2H), 3.14-3.09 (m, 2H),3.07-3.03 (m, 2H)

HPLCMS (Method D): [m/z]: 411.2 [M+H]⁺

2-(2-{[2-(4,5-Difluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 257)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (350 mg, 1.04 mmol),N-(2,3-difluoro-6-nitrophenyl)prop-2-enamide (K10) (250 mg, 1.10 mmol)and DBU (465 μl, 3.11 mmol) in MeCN (10 ml) gave an intermediate (193mg) after purification by flash column chromatography (eluting with agradient 0-20% MeOH/DCM). The intermediate was further reacted with ironpowder (88 mg, 1.57 mmol) in AcOH (2 ml) to give the title compound (14mg, 8%) as a pale yellow solid after purification by flash columnchromatography (eluting with a gradient of 0-30% MeOH/DCM) followed bybasic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.55-8.47 (m, 2H), 8.38 (d, J=4.6 Hz,1H), 7.74-7.67 (m, 1H), 7.44-7.36 (m, 1H), 7.23 (dd, J=8.8, 3.6 Hz, 1H),7.17-7.09 (m, 1H), 4.61 (d, J=4.8 Hz, 2H), 3.02-2.91 (m, 8H)

HPLCMS (Method G): [m/z]: 445.2 [M+H]⁺

2-(2-{[2-(4-Chloro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 226)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (340 mg, 1.01 mmol),N-(3-chloro-2-nitrophenyl)prop-2-enamide (H) (245 mg, 1.08 mmol) and DBU(147 μl, 0.98 mmol) in MeCN (10 ml) gave a crude intermediate which wasfurther reacted with iron powder (81 mg, 1.45 mmol) in AcOH (4 ml) togive the title compound (31 mg, 19%) as a white solid after purificationby basic prep-HPLC followed by flash column chromatography (eluting witha gradient of 0-40% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.51 (m, 2H), 8.38 (dt, J=4.6, 1.2 Hz,1H), 7.70 (ddd, J=10.0, 8.3, 1.2 Hz, 1H), 7.41 (m, 2H), 7.19 (dd, J=7.7,0.8 Hz, 1H), 7.12 (t, J=7.7 Hz, 1H), 4.62 (dd, J=5.6, 1.3 Hz, 2H),3.09-2.95 (m, 8H)

HPLCMS (Method C): [m/z]: 443.1 [M+H]⁺

N-[(3-fluoropyridin-2-yl)methyl]-2-(2-{[2-(4-methoxy-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-1,3-oxazole-4-carboxamide(Example Compound No. 227)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (301 mg, 0.89 mmol),N-(2-methoxy-6-nitrophenyl)prop-2-enamide (I) (198 mg, 0.89 mmol) andDBU (0.4 ml, 2.68 mmol) in MeCN (10 ml) gave a crude intermediate whichwas partially purified by flash column chromatography using a gradientelution of 0-10% MeOH in DCM. The intermediate was further reacted withiron powder (86 mg) in AcOH (3 ml) to give the title compound (2 mg, 1%)as a white solid after purification by basic prep-HPLC followed by flashcolumn chromatography (eluting with a gradient of 0-20% MeOH/DCM).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.30 (d, J=4.7 Hz, 1H), 8.26 (s, 1H),7.60-7.54 (m, 1H), 7.39-7.32 (m, 1H), 7.09 (t, J=8.0 Hz, 1H), 7.03 (d,1H), 6.70 (d, J=7.8 Hz, 1H), 4.65 (d, J=1.4 Hz, 2H), 3.93 (s, 3H),3.22-3.16 (m, 4H), 3.14-3.05 (m, 4H)

HPLCMS (Method G): [m/z]: 439.2 [M+H]⁺

2-(2-{[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 228)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (200 mg, 0.59 mmol),N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (198 mg, 0.89 mmol) and DBU(266 μl, 1.78 mmol) in MeCN (10 ml) gave an intermediate which waspartially purified by flash column chromatography with a gradientelution of 0-10% MeOH in DCM. The intermediate was further reacted withiron powder (114 mg) in AcOH (2 ml) to afford the title compound (10 mg,5%) as an off-white solid after purification by basic prep-HPLC followedby flash column chromatography (eluting with a gradient of 0-30%MeOH/DCM) and kp-NH flash chromatography (eluting with a gradient of0-4% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.53-8.45 (m, 2H), 8.39-8.35 (m, 1H),7.72-7.67 (m, 1H), 7.42-7.37 (m, 1H), 7.26 (d, J=8.0 Hz, 1H), 7.11-7.05(m, 1H), 6.93-6.88 (m, 1H), 4.61 (d, J=4.4 Hz, 2H), 3.01-2.91 (m, 8H)

HPLCMS (Method G): [m/z]: 427.1 [M+H]⁺

2-(2-{[2-(7-Chloro-4-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 247)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (300 mg, 0.89 mmol),N-(6-chloro-3-fluoro-2-nitrophenyl)prop-2-enamide (K2) (272 mg, 0.89mmol) and DBU (0.398 ml, 2.67 mmol) in MeCN (15 ml) gave a crudeintermediate which was purified by flash column chromatography using anelution gradient 0-15% MeOH in DCM. The intermediated was furtherreacted with iron powder (145 mg) in AcOH (3 ml) to give the titlecompound (7 mg, 2%) as a beige solid after purification by flash columnchromatography (eluting with a gradient of 0-35% MeOH/DCM) followed bykp-NH column chromatography (eluting with a gradient of 0-15% MeOH/DCM)and basic prep-HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.34 (d, J=4.7 Hz, 1H), 8.27 (s, 1H),7.63-7.56 (m, 1H), 7.42-7.36 (m, 1H), 7.16 (dd, J=8.6, 3.9 Hz, 1H), 6.93(dd, J=10.2, 8.6 Hz, 1H), 4.71 (d, J=1.6 Hz, 2H), 3.16-3.11 (m, 6H),3.07-3.03 (m, 2H)

HPLCMS (Method D): [m/z]: 461.1 [M+H]⁺

2-(2-{[2-(4,6-Difluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 249)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (500 mg, 1.48 mmol),N-(2,4-difluoro-6-nitrophenyl)prop-2-enamide (K4) (338 mg, 1.48 mmol)and DBU (0.664 ml, 4.45 mmol) in MeCN (15 ml) gave a crude intermediatewhich was partially purified by flash column chromatography using agradient of 0-20% MeOH in DCM. The intermediate was further reacted withiron powder (145 mg) in AcOH (4 ml) to give the title compound (23 mg,8%) as an off-white solid after purification by flash columnchromatography (eluting with a gradient of 0-40% MeOH/DCM) followed bykp-NH flash chromatography (eluting with a gradient of 0-5% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.53-8.46 (m, 2H), 8.41-8.36 (m, 1H),7.73-7.67 (m, 1H), 7.43-7.37 (m, 1H), 7.14 (dd, J=8.9, 2.2 Hz, 1H), 6.96(td, J=10.7, 2.2 Hz, 1H), 4.62 (dd, J=5.7, 1.4 Hz, 2H), 3.02-2.90 (m,8H)

HPLCMS (Method G): [m/z]: 445.2 [M+H]⁺

2-(2-{[2-(5-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 250)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (1.07 g, 2.59 mmol, 82% purity),N-(5-fluoro-2-nitrophenyl)prop-2-enamide (J) (0.54 g, 2.59 mmol) and DBU(1.28 ml, 8.54 mmol) in MeCN (30 ml) at room temperature for 20 h gave acrude mixture of mono:bis-alkylated (1:1.4) adducts (1.1 g) which wasfurther reacted with iron powder (0.52 g) in AcOH (8 ml) to give thetitle compound (90 mg, 9%) as a brown solid after purification by flashcolumn chromatography (eluting with a gradient of 0-30% MeOH/DCM),followed by kp-NH flash column chromatography (eluting with a gradientof 0-2% MeOH/DCM), then by flash column chromatography (eluting with agradient of 0-20% MeOH/DCM) and basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.52-8.47 (m, 2H), 8.39-8.36 (m, 1H),7.72-7.66 (m, 1H), 7.46-7.36 (m, 2H), 7.24 (dd, J=9.6, 2.3 Hz, 1H),6.99-6.89 (m, 1H), 4.61 (dd, J=5.7, 1.3 Hz, 2H), 3.02-2.89 (m, 8H)

HPLCMS (Method C): [m/z]: 427.2 [M+H]⁺

2-(2-{[2-(4,7-Difluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 251)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (400 mg, 1.19 mmol),N-(3,6-difluoro-2-nitrophenyl)prop-2-enamide (K6) (316 mg, 1.20 mmol)and DBU (0.53 ml, 3.56 mmol) in MeCN (15 ml) gave a crude intermediatewhich was partially purified by flash column chromatography using agradient elution of 0-20% MeOH in DCM. This intermediate was furtherreacted with iron powder (230 mg) in AcOH (4 ml) to give the titlecompound (63 mg, 14%) as an off-white solid after purification by flashcolumn chromatography (eluting with a gradient of 0-40% MeOH/DCM)followed by kp-NH flash chromatography (eluting with a gradient of 0-5%MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.52-8.46 (m, 2H), 8.38 (m, 1H),7.74-7.66 (m, 1H), 7.44-7.37 (m, 1H), 6.95-6.91 (m, 2H), 4.62 (dd,J=5.6, 1.4 Hz, 2H), 3.03-2.90 (m, 8H).

HPLCMS (Method G): [m/z]: 445.2 [M+H]⁺

N-[(3-fluoropyridin-2-yl)methyl]-2-[2-({2-[4-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]ethyl}amino)ethyl]-1,3-oxazole-4-carboxamide(Example Compound No. 256)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (300 mg, 0.89 mmol),N-[2-nitro-6-(trifluoromethyl)phenyl]prop-2-enamide (K8) (272 mg, 0.90mmol) and DBU (398 μl, 2.67 mmol) in MeCN (10 ml) gave a crudeintermediate which was partially purified by flash column chromatographyusing a gradient of 0-10% MeOH in DCM. The intermediate was furtherreacted with iron powder (177 mg) in AcOH (3 ml) to give the titlecompound (99 mg, 26%) as a yellow solid after purification by flashcolumn chromatography (eluting with a gradient of 0-25% MeOH/DCM)followed by kp-NH flash chromatography (eluting with a gradient of 0-6%MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.53-8.47 (m, 2H), 8.40-8.37 (m, 1H),7.75 (d, J=8.0 Hz, 1H), 7.73-7.67 (m, 1H), 7.45 (d, J=7.6 Hz, 1H),7.43-7.38 (m, 1H), 7.28 (t, J=7.8 Hz, 1H), 4.62 (d, J=4.7 Hz, 2H), 3.01(s, 4H), 3.00-2.93 (m, 4H)

HPLCMS (Method G): [m/z]: 477.4 [M+H]⁺

2-(2-{[2-(4-fluoro-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide(Example Compound No. 236)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamidedihydrochloride (236) (350 mg, 0.95 mmol),N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (206 mg, 0.95 mmol), DBU(1.0 ml, 2.85 mmol) in MeCN (15 ml) gave a crude mixture which waspartially purified by flash column chromatography (eluting with agradient of 0-15% MeOH/DCM). The mixture was further reacted with ironpowder (136 mg) in AcOH (4 ml) to afford the title compound (9 mg, 4%)as a pale brown solid after purification by flash column chromatography(eluting with a gradient of 0-40% MeOH/DCM), kp-NH flash columnchromatography (eluting with a gradient of 0-10% MeOH/DCM) and basicprep-HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.52-8.47 (m, 1H), 8.28 (s, 1H), 7.80(td, J=7.7, 1.8 Hz, 1H), 7.39 (d, J=7.9 Hz, 1H), 7.34-7.30 (m, 1H), 7.28(d, J=8.0 Hz, 1H), 7.19-7.10 (m, 1H), 6.96-6.88 (m, 1H), 4.65 (s, 2H),3.17-3.08 (m, 6H), 3.08-3.02 (m, 2H)

HPLCMS (Method D): [m/z]: 409.1 [M+H]⁺

Methyl2-(3-{[(tert-butoxy)carbonyl]amino}propanamido)-3-hydroxybutanoate (315)

In a similar fashion to general procedure 13, methyl L-threoninatehydrochloride (1:1) (11 g, 64.9 mmol),N-(tert-butoxycarbonyl)-beta-alanine (12.3 g, 64.9 mmol), TEA (9.94 ml,71.3 mmol) and DCC (14.7 g, 71.3 mmol) in DCM (250 ml) afforded thetitle compound (16.4 g, 72.4%, 87% purity) as a viscous yellow oil afterpurification by flash column chromatography (eluting with a gradient of0-100% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=6.35 (s, 1H), 5.12 (s, 1H), 4.59 (dd,J=8.8, 2.5 Hz, 1H), 4.36 (qd, J=6.4, 2.5 Hz, 1H), 3.78 (s, 3H), 3.45 (q,J=5.9 Hz, 2H), 2.57-2.46 (m, 2H), 1.43 (s, 9H), 1.23 (d, J=6.4 Hz, 3H)

HPLCMS (Method A): [m/z]: 291.05 [M+H]⁺

Methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate(316)

In a similar fashion to general procedure 14, methyl2-(3-{[(tert-butoxy)carbonyl]amino}propanamido)-3-hydroxybutanoate (315)(1 g, 2.87 mmol, 87% purity), DAST (0.45 ml, 3.44 mmol) and K₂CO₃ (0.79g, 5.73 mmol) in anhydrous DCM (25 ml) gave the title compound (0.61 g,67%) as a pale yellow oil after purification by flash columnchromatography (eluting with a gradient of 0-100% EtOAc/heptane).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.22 (br s, 1H), 4.87 (dq, J=9.9, 6.3Hz, 1H), 4.76 (dt, J=10.1, 1.2 Hz, 1H), 3.76 (s, 3H), 3.52-3.37 (m, 2H),2.53-2.44 (m, 2H), 1.44 (s, 9H), 1.29 (d, J=6.3 Hz, 3H)

Methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-oxazole-4-carboxylate(317)

In a similar fashion to general procedure 15, methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-4,5-dihydro-1,3-oxazole-4-carboxylate(316) (0.61 g, 1.98 mmol), bromo(trichloro)methane (0.59 ml, 5.95 mmol)and DBU (0.89 ml, 5.95 mmol) in DCM (15 ml) gave the title compound(0.42 g, 71%) as a dark orange oil which solidified on standing afterpurification by flash column chromatography (eluting with a gradient of0-100% EtOAc/heptane).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=4.94 (s, 1H), 3.90 (s, 3H), 3.55 (q,J=6.2 Hz, 2H), 2.93 (t, J=6.3 Hz, 2H), 2.59 (s, 3H), 1.42 (s, 9H)

HPLCMS (Method A): [m/z]: 284.95 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-oxazole-4-carboxylicacid (318)

In a similar fashion to general procedure 5, methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-oxazole-4-carboxylate(317) (0.42 g, 1.42 mmol), LiOH (0.067 g, 2.84 mmol) in THF (8 ml) andwater (2 ml) gave the title compound (0.4 g, 98%) as a pale orange oilwhich solidified on standing.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=12.72 (s, 1H), 6.90 (t, J=5.5 Hz, 1H),3.25 (d, J=6.2 Hz, 2H), 2.79 (t, J=6.9 Hz, 2H), 1.34 (s, 9H) [CH₃ peakobscured by DMSO peak]

HPLCMS (Method A): [m/z]: 293.00 [M+Na]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1,3-oxazol-2-yl)ethyl]carbamate(319)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1,3-oxazole-4-carboxylicacid (318) (0.4 g, 1.39 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.415 g, 2.09 mmol), DIPEA (0.8 ml, 4.59 mmol) andHATU (0.79 g, 2.09 mmol) in DMF (6 ml) gave the title compound (0.653 g,79%, 64% purity) as a yellow oil after purification by flash columnchromatography (eluting with a gradient of 0-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.44-8.30 (m, 2H), 7.75-7.64 (m, 1H),7.46-7.34 (m, 1H), 6.97 (br s, 1H), 4.60 (d, J=4.2 Hz, 2H), 3.34-3.24(m, 2H), 2.83 (t, J=6.8 Hz, 2H), 1.35 (s, 9H)

HPLCMS (Method A): [m/z]: 379.05 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-oxazole-4-carboxamidedihydrochloride (320)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1,3-oxazol-2-yl)ethyl]carbamate(319) (0.65 g, 1.10 mmol, 64% purity) and 12M HCl (1.16 ml, 11.04 mmol)in MeOH (10 ml) gave the title compound (0.51 g, 76% purity) as ahygroscopic off-white solid. The compound was used in the next stepwithout further purification.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.55 (dd, J=5.3, 1.0 Hz, 1H), 8.22-8.10(m, 1H), 7.86-7.75 (m, 1H), 3.70 (dd, J=11.2, 7.3 Hz, 3H), 3.43 (t,J=6.5 Hz, 2H), 3.17 (t, J=6.5 Hz, 2H), 2.58 (s, 3H) [CH₂ peak obscuredby the H₂O]

HPLCMS (Method A): [m/z]: 279.2 [M+H]⁺

N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-2-[2-({2-[(2-nitrophenyl)carbamoyl]ethyl}amino)ethyl]-1,3-oxazole-4-carboxamide(Example Compound No. 230)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1,3-oxazole-4-carboxamidedihydrochloride (320) (0.51 g, 1.11 mmol, 76% purity),N-(2-nitrophenyl)prop-2-enamide (D) (0.4 g, 2.09 mmol) and DBU (0.69 ml,4.59 mmol) in MeCN (15 ml) at room temperature for 20 h gave a mixtureof mono:bis-alkylated (1:3.6) adducts which was further reacted withiron powder (0.31 g) in AcOH (3.5 ml) to give the title compound (0.12g, 20%) as a pale green solid after purification by flash columnchromatography (eluting with a gradient of 0-30% MeOH/DCM), followed byflash column chromatography (KP—NH, eluting with a gradient of 0-5%MeOH/DCM) and a final purification by flash column chromatography(eluting with a slow gradient of 0-30% MeOH/DCM).

1H-NMR (MeOD, 250 MHz): d[ppm]=8.33-8.30 (d, J=4.7 Hz, 1H), 7.60-7.54(m, 1H), 7.48-7.40 (m, 2H), 7.38-7.33 (m, 1H), 7.18-7.14 (m, 2H), 4.65(d, J=1.6 Hz, 2H), 3.15-3.07 (m, 6H), 2.97 (t, J=6.6 Hz, 2H), 2.52 (s,3H)

HPLCMS (Method C): [m/z]: 423.1 [M+H]⁺

General Scheme 12 Above2-(2-{[2-(5-cyano-1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 265)

In a similar fashion to general procedure 8,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (235) (400 mg, 1.19 mmol) andN-(4-cyano-2-nitrophenyl)prop-2-enamide (K12) (325 mg, 1.49 mmol) andDBU (0.53 ml, 3.56 mmol) in MeCN (12 ml) gave a crude intermediate whichwas further reacted with iron powder (239 mg, 4.28 mmol) in AcOH (4 ml)to afford the title compound (24 mg, 5%) as a brown solid afterpurification by flash column chromatography (eluting with a gradient of0-20% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.51-8.46 (m, 2H), 8.39-8.36 (m, 1H),8.01-7.95 (m, 1H), 7.72-7.67 (m, 1H), 7.63-7.59 (m, 1H), 7.50 (dd,J=8.3, 1.5 Hz, 1H), 7.42-7.38 (m, 1H), 4.63-4.59 (m, 2H), 3.02-2.91 (m,8H)

HPLCMS (Method B): [m/z]: 434.2 [M+H]⁺

General Scheme 13 Above Methyl1-(cyanomethyl)-1H-1,2,4-triazole-3-carboxylate (239)

Methyl 1H-1,2,4-triazole-3-carboxylate (5 g, 39.34 mmol) and2-bromoacetonitrile (2.7 ml, 39.34 mmol) in DMF (45 ml) were stirred for5 min. K₂CO₃ (5.44 g, 39.34 mmol) was added and the reaction stirred atroom temperature for 23 h. The solvent was evaporated under vacuum,water (20 ml) added and the aqueous layer extracted with EtOAc (8×50ml). The combined organic layers were washed with 5% aqueous LiCl (2×20ml), brine (2×20 ml), dried (MgSO4), filtered and evaporated to give amixture of regioisomers (1.5:1) as a dark brown oil (5.27 g). The crudematerial was purified by flash column chromatography (eluting with agradient of 10 to 100% EtOAc/heptane) to give the title compound (3.5 g,45%) as a pale brown oil which solidified on standing.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.30 (s, 1H), 5.79 (s, 2H), 3.94 (s,3H)

Methyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylate(240)

Methyl 1-(cyanomethyl)-1H-1,2,4-triazole-3-carboxylate (239) (1 g, 6.02mmol), di-tert-butyl dicarbonate (2.63 g, 12.04 mmol) and TEA (1.7 ml,12.04 mmol) in EtOH (30 ml) were stirred for 5 min before 10% palladiumon carbon (128 mg, 0.602 mmol) was added. The reaction was stirred undera hydrogen atmosphere for 18 h. The reaction mixture was filteredthrough celite and the residue washed with EtOH (30 ml). The filtratewas evaporated to give a brown oil which began crystallising on standing(1.95 g). Purification by flash column chromatography (eluting with agradient of 0 to 100% EtOAc/heptane) gave the title compound (1.35 g,69.7%) as a pale brown solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.13 (s, 1H), 4.69 (br s, 1H), 4.40 (t,J=5.6 Hz, 2H), 4.00 (s, 3H), 3.60 (app q, J=5.9 Hz, 2H), 1.42 (s, 9H)

HPLCMS (Method A): [m/z]: 271.1 [M+H]⁺

1-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylicacid (241)

In a similar fashion using general procedure 5, LiOH (0.11 g, 4.72 mmol)and methyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylate(240) (0.87 g, 2.69 mmol) in THF (20 ml)/water (5 ml) gave the titlecompound (0.71 g, 100%) as a cream solid. The compound was used in thenext step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.54 (s, 1H), 6.97 (br s, 1H), 4.26(t, J=5.9 Hz, 2H), 3.34 (app q, J=5.8 Hz, 2H) obscured by H₂O peak, 1.34(s, 9H)

HPLCMS (Method A): [m/z]: 257.05 [M+H]⁺

Tert-butylN-[2-(3-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-1,2,4-triazol-1-yl)ethyl]carbamate(242)

In a similar fashion using general procedure 6,1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylicacid (241) (0.5 g, 1.95 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.58 g, 2.93 mmol), DIPEA (1.7 ml, 9.76 mmol),HATU (1.11 g, 2.93 mmol) in DMF (10 ml) gave the title compound (0.55 g,76%) as an off-white solid after purification by flash columnchromatography (eluting with a gradient 0 to 10% MeOH/DCM) followed by asecond flash column chromatography (eluting with a gradient 0 to 10%MeOH/EtOAc).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.74 (t, J=5.6 Hz, 1H), 8.57 (s, 1H),8.39 (d, J=4.6 Hz, 1H), 7.78-7.63 (m, 1H), 7.42 (dt, J=8.6, 4.4 Hz, 1H),7.00 (s, 1H), 4.64 (d, J=4.7 Hz, 2H), 4.28 (t, J=5.9 Hz, 2H), 3.36 (appq, J=5.9 Hz, 2H), 1.35 (s, 9H)

HPLCMS (Method A): [m/z]: 365.15 [M+H]⁺

Tert-butylN-[2-(3-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1H-1,2,4-triazol-1-yl)ethyl]carbamate(243)

In a similar fashion using general procedure 6,1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,2,4-triazole-3-carboxylicacid (241) (0.58 g, 2.26 mmol), (3-chloropyridin-2-yl)methanaminedihydrochloride (0.732 g, 3.4 mmol), HATU (1.29 g, 3.4 mmol), DIPEA(1971 μl, 11.32 mmol) in DMF (11 ml) gave the title compound (0.87 g,96%) as a brown foam after purification by flash column chromatographyeluting with a gradient of 0 to 10% MeOH/DCM.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.73 (t, J=5.3 Hz, 1H), 8.57 (s, 1H),8.52 (d, J=4.4 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.39 (dd, J=8.0, 4.7 Hz,1H), 7.00 (s, 1H), 4.67 (d, J=5.4 Hz, 2H), 4.28 (t, J=5.9 Hz, 2H), 3.36(app q, J=6.1 Hz, 2H), 1.35 (s, 9H)

HPLCMS (Method A): [m/z]: 381.05 [M+H]⁺

1-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamidedihydrochloride (244)

In a similar fashion using general procedure 2, 12 M HCl (2.48 ml) andtert-butylN-[2-(3-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-1,2,4-triazol-1-yl)ethyl]carbamate(242) (0.54 g, 1.49 mmol) in MeOH (10 ml) at 40° C. for 2 h gave thetitle compound (0.52 g, 100%) as an off-white foam. The compound wasused in the next step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.89 (t, J=5.6 Hz, 1H), 8.70 (s, 1H),8.39 (d, J=4.7 Hz, 1H), 8.25 (s, 3H), 7.80-7.67 (m, 1H), 7.43 (dt,J=8.6, 4.5 Hz, 1H), 4.66 (d, J=4.4 Hz, 2H), 4.55 (t, J=5.9 Hz, 2H), 3.32(q, J=5.6 Hz, 2H)

HPLCMS (Method A): [m/z]: 265.05 [M+H]⁺

1-(2-Aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamidedihydrochloride (245)

In a similar fashion using general procedure 2, 12 M HCl (3.6 ml) andtert-butylN-[2-(3-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1H-1,2,4-triazol-1-yl)ethyl]carbamate(243) (0.87 g, 2.17 mmol) in MeOH (15 ml) at 40° C. for 3 h gave thetitle compound (0.84 g, 99%) as a pale orange foam.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.89 (t, J=5.5 Hz, 1H), 8.74 (s, 1H),8.53 (dd, J=4.7, 1.3 Hz, 1H), 8.35 (s, 3H), 7.99 (dd, J=8.1, 1.4 Hz,1H), 7.42 (dd, J=8.1, 4.7 Hz, 1H), 4.69 (d, J=5.5 Hz, 2H), 4.58 (t,J=5.9 Hz, 2H), 3.33 (q, J=5.8 Hz, 2H), 3.17 (s, 1H), 2.69 (s, 1H)

HPLCMS (Method A): [m/z]: 280.95 [M+H]⁺

1-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamide (Example Compound No.169)

In a similar fashion using general procedure 3,1H-1,3-Benzodiazole-2-carbaldehyde (104 mg, 0.71 mmol),1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamidedihydrochloride (244) (200 mg, 0.59 mmol) and DIPEA (0.41 ml, 2.37 mmol)in MeOH (8 ml) at room temperature for 17 h, followed by addition ofNaBH₄ (32 mg, 0.86 mmol) gave the title compound (79 mg, 34%) as a beigesolid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.76 (t, J=5.6 Hz, 1H),8.65 (s, 1H), 8.38 (d, J=4.7 Hz, 1H), 7.70 (app t, J=9.3 Hz, 1H), 7.49(br d, J=38.6 Hz, 2H), 7.40-7.43 (m, 1H), 7.12 (d, J=3.7 Hz, 2H), 4.64(d, J=5.5 Hz, 2H), 4.34 (t, J=6.0 Hz, 2H), 3.92 (s, 2H), 3.02 (t, J=5.9Hz, 2H)

HPLCMS (Method C): [m/z]: 395.2 [M+H]⁺

1-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamide(Example Compound No. 181)

In a similar fashion using general procedure 8, DBU (0.39 ml, 2.58mmol),1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamidedihydrochloride (244) (300 mg, 0.86 mmol) andN-(2-nitrophenyl)prop-2-enamide (D) (165 mg, 0.86 mmol) in MeCN (14 ml)at room temperature for 16 h, gave the crude intermediate (0.364 g) as amixture of mono:bis-alkylated (2:1) adducts. The mixture was dissolvedin AcOH (5 ml), iron (112 mg) was added and the reaction heated to 80°C. for 4 h to give the title compound (20 mg, 11%) as an off-white solidafter purification by basic prep-HPLC followed by flash columnchromatography (×2) (KP—NH, eluting with a gradient 0-30% MeOH/DCM and5-20% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz) d[ppm]=12.14 (s, 1H), 8.75 (t, J=5.6 Hz, 1H),8.59 (s, 1H), 8.41-8.35 (m, 1H), 7.73-7.67 (m, 1H), 7.45 (br s, 2H),7.43-7.38 (m, 1H), 7.13-7.07 (m, 2H), 4.64 (dd, J=5.6, 1.3 Hz, 2H), 4.31(t, J=6.0 Hz, 2H), 2.99 (dt, J=12.3, 6.0 Hz, 4H), 2.94-2.89 (m, 2H)

HPLCMS (Method C): [m/z]: 409.3 [M+H]⁺

1-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamide(Example Compound No. 170)

In a similar fashion using general procedure 3,1H-1,3-Benzodiazole-2-carbaldehyde (156 mg, 1.07 mmol),1-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-1,2,4-triazole-3-carboxamidedihydrochloride (245) (350 mg, 0.89 mmol) and DIPEA (0.62 ml, 3.56 mmol)in MeOH (10 ml) at 40° C. for 2 h, followed by addition of NaBH₄ (50.5mg, 1.34 mmol) added gave the title compound (190 mg, 52%) as a creamsolid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.75 (t, J=5.4 Hz, 1H),8.66 (s, 1H), 8.51 (dd, J=4.7, 1.1 Hz, 1H), 7.95 (dd, J=8.1, 1.2 Hz,1H), 7.49 (br d, J=37.6 Hz, 2H), 7.39 (dd, J=8.0, 4.7 Hz, 1H), 7.12 (s,2H), 4.67 (d, J=5.4 Hz, 2H), 4.35 (t, J=6.0 Hz, 2H), 3.93 (s, 2H), 3.03(t, J=5.9 Hz, 2H)

HPLCMS (Method C): [m/z]: 411.3 [M+H]⁺

General Scheme 14 Above Methyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylate(246)

DIAD (9.39 ml, 43.61 mmol) was added dropwise to an ice-cooled solutionof methyl 1H-pyrazole-4-carboxylate (5 g, 39.65 mmol), tert-butyl(2-hydroxyethyl)carbamate (6.13 ml, 39.65 mmol) and PPh₃ (11.44 g, 43.61mmol) in THF (300 ml). The reaction was then allowed to warm to roomtemperature and stirred for 1.5 h. The reaction mixture was quenchedwith water (150 ml) and the layers separated. The aqueous layer wasextracted using EtOAc (3×150 ml). The combined organic layers werewashed with brine, dried (MgSO₄), filtered and the solvent evaporated togive the crude product. Purification by flash column chromatography(eluting with a gradient of 15-100% EtOAc/heptane) gave the titlecompound (11.3 g, 68%) as a white solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=7.93 (s, 1H), 7.87 (s, 1H), 4.25 (t,J=5.3 Hz, 2H), 3.83 (s, 3H), 3.61-3.54 (m, 2H), 1.44 (s, 9H)

HPLCMS (Method A): [m/z]: 270.1 [M+H]⁺

Ethyl 1-(cyanomethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (247)

A mixture of ethyl 3,5-dimethyl-1H-pyrazole-4-carboxylate (2 g, 11.89mmol), bromoacetonitrile (1.24 ml, 17.84 mmol), K₂CO₃ (3.29 g, 23.78mmol) and acetone (6 ml) was heated at 10000 under microwave irradiationfor 1 h. Further bromoacetonitrile (0.828 ml, 11.89 mmol) was added andthe mixture was heated at 1000 under microwave irradiation for a further1 h. The reaction mixture was concentrated in vacuo, the residue wastaken up in water (100 ml) and extracted with EtOAc (5×50 ml). Thecombined organic extracts were dried (MgSO₄), filtered and evaporated invacuo. Purification by flash column chromatography using an elutiongradient 0-20% MeOH/DCM afforded the title compound (2.22 g, 71%) as anorange solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=5.42 (s, 2H), 4.21 (q, J=7.1 Hz, 2H),2.50 (s, 3H), 2.30 (s, 3H), 1.28 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 207.95 [M+H]⁺

Ethyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate(248)

A suspension of ethyl1-(cyanomethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate (247) (2.22 g,9.64 mmol), BOC anhydride (4.21 g, 19.27 mmol), TEA (2.69 ml, 19.27mmol) and palladium on carbon (10% wt, 0.103 g, 0.964 mmol) in EtOH (100ml) was stirred under an atmosphere of hydrogen for 28 h. The reactionmixture was filtered and the residue rinsed with MeOH. The combinedfiltrates were evaporated in vacuo and the residue partitioned betweenwater (100 ml) and EtOAc (50 ml). The phases were separated and theaqueous phase extracted with EtOAc (3×50 ml). The combined organiclayers were dried (MgSO₄), filtered and evaporated in vacuo.Purification by flash column chromatography using an elution gradient70-100% EtOAc/heptane afforded the title compound (1.52 g, 51%) as ayellow-brown solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=6.90 (s, 1H), 4.18 (q, J=7.1 Hz, 2H),4.02 (t, J=6.1 Hz, 2H), 3.21 (q, J=6.1 Hz, 2H), 2.42 (s, 3H), 2.27 (s,3H), 1.38-1.28 (s, 9H), 1.26 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 312.45 [M+H]⁺

Ethyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate(248)

A solution of ethyl 3-(trifluoromethyl)-1H-pyrazole-4-carboxylate (3 g,14.41 mmol), tert-butyl (2-hydroxyethyl)carbamate (2.45 ml, 15.85 mmol)and PPh₃ (4.16 g, 15.85 mmol) in THF (50 ml) was stirred at roomtemperature for 16 h. Additional (2-hydroxyethyl)carbamate (2.45 ml,15.85 mmol) was added and the reaction stirred at room temperature for afurther 48 h. The reaction was quenched with water (30 ml) and extractedinto EtOAc (3×50 ml). The combined organic layers were washed with brine(30 ml), dried (MgSO₄), filtered and evaporated gave a yellow oil.Purification by flash column chromatography (eluting with a gradient of5-80% TBME/heptane) gave a residue which was re-purified by flash columnchromatography (eluting with a gradient of 5-60% TBME/heptane) providingthe title compound (1.19 g, 21%) as a white solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=7.97 (s, 1H), 4.72 (br s, 1H), 4.32 (q,J=7.1 Hz, 2H), 4.32-4.27 (m, 2H), 3.59 (app q, J=5.9 Hz, 2H), 1.44 (s,9H), 1.35 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 374 [M+Na]⁺

1-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid(249)

In a similar fashion to general procedure 5, LiOH (0.72 g, 30.08 mmol)and 1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylate(246) (54%, 5 g, 10.03 mmol) in THF (80 ml) and water (30 ml) at roomtemperature for 24 h gave the title compound (2.6 g, 96.5%). Compoundwas used without purification.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.06 (s, 1H), 7.87 (s, 1H), 4.23(t, J=5.8 Hz, 2H), 3.46 (app q, J=5.5 Hz, 2H), 1.42 (d, J=19.0 Hz, 9H)

HPLCMS (Method A): [m/z]: 255.95 [M+H]⁺

1-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylicacid (250)

In a similar fashion to general procedure 5, ethyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylate(247) (1 g, 2.58 mmol, 80% purity) and LiOH (0.37 g, 15.49 mmol) in THF(60 ml) and water (30 ml) at 70° C. afforded the title compound (0.417g, 52%, 90% purity) as a yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.02 (s, 1H), 6.91 (t, J=5.6 Hz, 1H),4.00 (t, J=6.0 Hz, 2H), 3.21 (q, J=6.0 Hz, 2H), 2.40 (s, 3H), 2.26 (s,3H), 1.37 (s, 9H)

HPLCMS (Method A): [m/z]: 284.05 [M+H]⁺

1-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylicacid (251)

In a similar fashion to general procedure 5, LiOH (0.241 g, 10.08 mmol)and ethyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate(248) (89%, 1.18 g, 2.99 mmol) in THF/water (25 ml/8 ml) at roomtemperature for 16 h gave the title compound (0.54 g, 45%) as a whitesolid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.03 (s, 1H), 4.80 (br s, 1H), 4.36-4.18(br m, 2H), 3.71-3.54 (m, 2H), 1.45 (s, 9H)

HPLCMS (Method A): [m/z]: 346.1 [M+Na]⁺

Tert-butylN-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1H-pyrazol-1-yl}ethyl)carbamate(252)

In a similar fashion using general procedure 6,1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid(249) (0.50 g, 1.96 mmol), 1-(pyridin-2-yl)methanamine (0.30 ml, 2.94mmol), DIPEA (1.0 ml, 5.88 mmol) and HATU (1.12 g, 2.94 mmol) in DCM (30ml) gave the title compound (0.647 g, 56%, 59% purity) as a yellow oilafter purification by flash column chromatography (eluting with agradient of 3:2 EtOAc/heptane and 100% EtOAc). The compound was used inthe next step without further purification.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.56 (d, J=4.4 Hz, 1H), 7.87 (d, J=3.8Hz, 2H), 7.68 (td, J=7.7, 1.8 Hz, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.24-7.20(m, 1H), 7.14 (s, 1H), 4.84 (s, 1H), 4.71 (d, J=4.8 Hz, 2H), 4.25 (t,J=5.4 Hz, 2H), 3.58 (q, J=5.4 Hz, 2H), 1.43 (s, 9H)

HPLCMS (Method A): [m/z]: 346.3 [M+H]⁺

Tert-butylN-{2-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1H-pyrazol-1-yl]ethyl}carbamate(253)

In a similar fashion using general procedure 6,1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid(249) (0.7 g, 2.74 mmol), 5H,6H,7H-cyclopenta[b]pyridin-7-aminehydrochloride (0.7 g, 4.11 mmol), DIPEA (1.4 ml, 8.23 mmol) and HATU(1.56 g, 4.11 mmol) in DMF (15 ml) gave the title compound (0.709 g,70%) as an off-white solid after purification by flash columnchromatography (eluting with a gradient of 80-100% EtOAc/heptane).

1H-NMR (MeOD-d6, 500 MHz): d[ppm]=8.35 (d, J=4.6 Hz, 1H), 8.07 (s, 1H),7.94 (s, 1H), 7.73 (d, J=7.8 Hz, 1H), 7.28 (dd, J=7.6, 5.0 Hz, 1H), 5.53(t, J=8.1 Hz, 1H), 4.23 (t, J=5.7 Hz, 2H), 3.49-3.43 (m, 2H), 3.13-3.03(m, 1H), 2.95 (dt, J=16.8, 8.5 Hz, 1H), 2.66 (ddt, J=11.3, 8.1, 3.9 Hz,1H), 2.07-1.95 (m, 1H), 1.40 (s, 9H)

HPLCMS (Method A): [m/z]: 372.1 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate(254)

In a similar fashion using general procedure 6,1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid(249) (0.35 g, 1.3 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.46 g, 1.95 mmol), DIPEA (1.13 ml, 6.51 mmol) andHATU (0.74 g, 1.95 mmol) in DMF (7 ml) gave the title compound (0.4 g,82%) as an orange foam after purification by flash column chromatography(eluting with a gradient of 0-50% MeOH/EtOAc).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.40-8.37 (m, 1H), 7.89 (s, 2H),7.46-7.38 (m, 1H), 7.30-7.24 (m, 1H), 4.86 (br s, 1H), 4.78 (dd, J=4.4and 1.2 Hz, 2H), 4.26 (t, J=5.3 Hz, 2H), 3.64-3.50 (m, 2H), 1.43 (s, 9H)

HPLCMS (Method A): [m/z]: 364.40 [M+H]⁺

Tert-butylN-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate(255)

In a similar fashion using general procedure 6,1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-pyrazole-4-carboxylic acid(249) (0.7 g, 2.74 mmol), (3-chloropyridin-2-yl)methanaminedihydrochloride (0.89 g, 4.11 mmol), DIPEA (2.39 ml, 13.71 mmol) andHATU (1.56 g, 4.11 mmol) in DMF (15 ml) at room temperature for 24 h,gave the title compound (0.79 g, 76%) as a viscous brown oil afterpurification by flash column chromatography (eluting with a gradient of0-50% MeOH/EtOAc). The oil solidified on standing.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.48 (dd, J=4.7, 1.0 Hz, 1H), 7.91 (s,1H), 7.91 (s, 1H), 7.72 (dd, J=8.0, 1.2 Hz, 1H), 7.50 (br s, 1H), 7.23(dd, J=8.0, 4.8 Hz, 1H), 4.87 (br s, 1H), 4.78 (d, J=4.2 Hz, 2H), 4.26(t, J=5.3 Hz, 2H), 3.59 (app q, J=5.6 Hz, 2H), 1.44 (s, 9H)

HPLCMS (Method A): [m/z]: 380.4 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-3,5-dimethyl-1H-pyrazol-1-yl)ethyl]carbamate(256)

In a similar fashion to general procedure 6,1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3,5-dimethyl-1H-pyrazole-4-carboxylicacid (250) (0.42 g, 1.33 mmol, 90% purity),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.47 g, 2.0mmol), DIPEA (1.16 ml, 6.67 mmol) and HATU (0.76 g, 2.0 mmol) in THF (15ml) and DMF (3 ml) afforded the title compound (0.40 g, 77%) as acolourless glassy solid after purification by flash columnchromatography (kp-NH, eluting with a gradient of 60-100%EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.38 (d, J=4.7 Hz, 1H), 7.81-7.77 (m,1H), 7.71-7.65 (m, 1H), 7.39 (dt, J=8.6, 4.4 Hz, 1H), 6.94-6.89 (m, 1H),4.59 (d, J=4.3 Hz, 2H), 3.99 (t, J=6.5 Hz, 2H), 3.20 (q, J=6.5 Hz, 2H),2.34 (s, 3H), 2.25 (s, 3H), 1.37 (s, 9H)

HPLCMS (Method A): [m/z]: 392.1 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl]carbamate(257)

In a similar fashion using general procedure 6,1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylicacid (251) (90%, 0.54 g, 1.53 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.23 g, 1.8 mmol), DIPEA (0.87 ml, 5.01 mmol) andHATU (0.57 g, 1.5 mmol) in DMF (3 ml) and THF (15 ml) at roomtemperature for 72 h, gave the gave the title compound (0.646 g, 65%)after purification by flash column chromatography (eluting with agradient of 5-100% EtOAc/heptane).

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.40-8.35 (m, 1H), 7.98 (s, 1H), 7.56(s, 1H), 7.46-7.37 (m, 1H), 7.31-7.23 (m, 4H), 4.80 (dd, J=4.3, 1.2 Hz,2H), 4.30 (t, J=5.4 Hz, 2H), 3.60 (app q, J=6.0 Hz, 2H), 1.44 (s, 9H)

HPLCMS (Method A): [m/z]: 432.1 [M+H]⁺

1-(2-Aminoethyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamidedihydrochloride (258)

In a similar fashion using general procedure 2, 12 M HCl (6.5 ml) andtert-butylN-(2-{4-[(pyridin-2-ylmethyl)carbamoyl]-1H-pyrazol-1-yl}ethyl)carbamate(252) (0.647 g, 1.11 mmol, 59% pure) in MeOH (6.5 ml) at roomtemperature for 2.5 h, gave the title compound (0.513 g, quant.) as apale yellow oil. The compound was used in the next step without furtherpurification.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=9.16 (s, 1H), 8.77 (s, 1H), 8.33 (s,1H), 8.13 (s, 2H), 8.05 (s, 1H), 7.80 (s, 2H), 4.72 (s, 2H), 4.42 (s,2H), 3.27 (d, J=5.9 Hz, 2H), 3.05-2.78 (m, 3H)

HPLCMS (Method A): [m/z]: 246 [M+H]⁺

1-(2-Aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamidedihydrochloride (259)

In a similar fashion using general procedure 2, 12 M HCl (3.2 ml) andtert-butylN-{2-[4-({5H,6H,7H-cyclopenta[b]pyridin-7-yl}carbamoyl)-1H-pyrazol-1-yl]ethyl}carbamate(253) (0.709 g, 1.909 mmol) in MeOH (20 ml) at room temperature for 20h, gave the title compound (0.745 g, quant.) as a grey solid.

¹H NMR (500 MHz, Methanol-d4): d[ppm]=8.60 (d, J=5.8 Hz, 1H), 8.51 (d,J=7.8 Hz, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 7.93 (dd, J=7.7, 6.0 Hz, 1H),5.80 (t, J=8.4 Hz, 1H), 4.53-4.49 (m, 2H), 3.46 (t, J=5.7 Hz, 2H),3.39-3.35 (m, 1H), 3.18 (dt, J=17.0, 8.5 Hz, 1H), 2.83-2.74 (m, 1H),2.41-2.31 (m, 1H)

HPLCMS (Method A): [m/z]: 272.05 [M+H]⁺

1-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamidedihydrochloride (260)

In a similar fashion using general procedure 2, 12 M HCl (3.67 ml) andtert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate(254) (0.4 g, 1.1 mmol) in MeOH (5 ml) at room temperature for 16 h,gave the title compound (0.38 g, quant.) as a cream foam. The compoundwas used in the next step without further purification.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.65 (t, J=5.7 Hz, 1H), 8.38 (dt,J=4.6, 1.4 Hz, 1H), 8.25 (s, 1H), 8.12 (br s, 3H), 8.00-7.97 (m, 1H),7.73-7.68 (m, 1H), 7.43-7.39 (m, 1H), 4.59 (dd, J=5.6, 1.5 Hz, 2H), 4.40(t, J=6.1 Hz, 2H), 3.25 (app h, J=5.7 Hz, 2H)

HPLCMS (Method A): [m/z]: 264.05 [M+H]⁺

1-(2-Aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamidedihydrochloride (261)

In a similar fashion using general procedure 2, 12 M HCl (6.5 ml) andtert-butylN-[2-(4-{[(3-chloropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)ethyl]carbamate(255) (0.79 g, 1.97 mmol) in MeOH (10 ml) at room temperature for 25 h,gave the title compound (0.7 g, 95%) as a beige solid. The compound wasused in the next step without further purification.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.69 (dd, J=5.5, 1.2 Hz, 1H), 8.51(dd, J=8.3, 1.2 Hz, 1H), 8.26 (s, 1H), 8.05 (s, 1H), 7.86 (dd, J=8.3,5.5 Hz, 1H), 4.88 (s, 2H), 4.51 (t, J=5.6 Hz, 2H), 3.46 (t, J=5.6 Hz,2H)

HPLCMS (Method A): [m/z]: 279.9 [M+H]⁺

1-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxamidedihydrochloride (262)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-3,5-dimethyl-1H-pyrazol-1-yl)ethyl]carbamate(256) (0.4 g, 1.02 mmol) and 12 M HCl (1.7 ml) in MeOH (5 ml) affordedthe title compound (0.399 g, 93% purity) as a white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.64 (dd, J=5.5, 1.2 Hz, 1H), 8.33(t, J=8.9 Hz, 1H), 7.97-7.92 (m, 1H), 4.86-4.85 (m, 2H), 4.34-4.29 (m,2H), 3.40 (t, J=5.8 Hz, 2H), 2.46 (s, 3H), 2.38 (s, 3H)

HPLCMS (Method A): [m/z]: 292 [M+H]⁺

1-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamidedihydrochloride (263)

In a similar fashion using general procedure 2, 12 M HCl (2.1 ml) andtert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-3-(trifluoromethyl)-1H-pyrazol-1-yl)ethyl]carbamate(257) (80%, 0.68 g, 1.26 mmol) in MeOH (10 ml) at room temperature for17 h, gave the title compound (0.588 g, 93.4%) as a pink solid. Thecompound was used in the next step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.80 (t, J=5.7 Hz, 1H), 8.52 (s, 1H),8.42-8.36 (m, 1H), 8.23 (s, 3H), 7.78-7.68 (m, 1H), 7.48-7.39 (m, 1H),4.59 (dd, J=5.5, 1.3 Hz, 2H), 4.50 (t, J=6.0 Hz, 2H), 3.29 (q, J=5.7 Hz,2H), 2.89 (s, 1H), 2.69 (s, 7H)

HPLCMS (Method A): [m/z]: 332.2 [M+H]⁺

1-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide(Example Compound No. 92)

In a similar fashion using general procedure 3,1-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamidedihydrochloride (258) (256 mg, 0.805 mmol),1H-benzimidazole-2-carbaldehyde (129 mg, 0.885 mmol) and DIPEA (0.70 ml,4.02 mmol) in MeOH (7 ml) at room temperature for 65 h, followed byaddition of NaBH₄ (46 mg, 1.21 mmol) gave the title compound (58 mg,19%) as a pale yellow solid after purification by prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.68 (t, J=6.0 Hz, 1H),8.49 (d, J=4.2 Hz, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.74 (td, J=7.7, 1.8Hz, 1H), 7.51 (s, 1H), 7.45 (s, 1H), 7.29 (d, J=7.8 Hz, 1H), 7.25 (dd,J=7.1, 5.1 Hz, 1H), 7.18-7.05 (m, 2H), 4.49 (d, J=6.0 Hz, 2H), 4.22 (t,J=6.2 Hz, 2H), 3.91 (s, 2H), 2.97 (t, J=6.1 Hz, 2H), 2.45 (s, 1H)

HPLCMS (Method B): [m/z]: 376.2 [M+H]⁺

1-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamide(Example Compound No. 132)

In a similar fashion using general procedure 3,1-(2-aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamidedihydrochloride (259) (150 mg, 0.38 mmol),1H-benzimidazole-2-carbaldehyde (67 mg, 0.46 mmol) and DIPEA (0.267 ml,1.53 mmol) in MeOH (6 ml) at room temperature for 24 h, followed byaddition of NaBH₄ (22 mg, 0.57 mmol) gave the title compound (23 mg,15%) as a yellow solid after purification by basic prep-HPLC followed byflash column chromatography (kp-NH, eluting with a gradient of 0-20%MeOH/EtOAc).

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.35 (d, J=4.9 Hz, 1H), 8.17 (s,1H), 7.93 (s, 1H), 7.74 (d, J=7.6 Hz, 1H), 7.51 (s, 2H), 7.28 (dd,J=7.6, 4.9 Hz, 1H), 7.20 (dd, J=6.0, 3.2 Hz, 2H), 5.54 (t, J=8.2 Hz,1H), 4.29 (t, J=5.9 Hz, 2H), 4.01 (s, 2H), 3.09 (t, J=5.9 Hz, 2H),3.08-3.04 (m, 1H), 2.99-2.91 (m, 1H), 2.71-2.63 (m, 1H), 2.06-1.97 (m,1H)

HPLCMS (Method B): [m/z]: 402.1 [M+H]⁺

1-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide (Example Compound No. 145)

In a similar fashion using general procedure 3,1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamidedihydrochloride (260) (200 mg, 0.59 mmol),1H-benzimidazole-2-carbaldehyde (104 mg, 0.71 mmol) and DIPEA (0.41 ml,2.38 mmol) in MeOH (8 ml) at room temperature for 18 h, followed byaddition of NaBH₄ (32.7 mg, 0.87 mmol) gave the title compound (91 mg,40%) as a colourless film after purification by flash columnchromatography (kp-NH, eluting with a gradient of 0-10% MeOH/DCM)followed by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (br s, 1H), 8.53 (t, J=5.7 Hz,1H), 8.37 (dt, J=4.6, 1.4 Hz, 1H), 8.21 (s, 1H), 7.88 (s, 1H), 7.70-7.65(m, 1H), 7.59-7.41 (m, 2H), 7.41-7.37 (m, 1H), 7.12 (d, J=4.7 Hz, 2H),4.57 (dd, J=5.7, 1.6 Hz, 2H), 4.21 (t, J=6.2 Hz, 2H), 3.90 (br s, 2H),2.96 (app br s, 2H)

HPLCMS (Method C): [m/z]: 394.1 [M+H]⁺

1-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(Example Compound No. 138)

In a similar fashion using general procedure 3,1-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamidedihydrochloride (261) (200 mg, 0.54 mmol),1H-benzimidazole-2-carbaldehyde (94.5 mg, 0.65 mmol) and DIPEA (0.38 ml,2.16 mmol) in MeOH (8 ml) at room temperature for 16 h, followed byaddition of NaBH₄ (30.6 mg, 0.81 mmol) gave the title compound (127 mg,56%) as a pale green foam after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.51-8.46 (m, 2H), 8.23(s, 1H), 7.92 (dd, J=8.1, 1.4 Hz, 1H), 7.90 (s, 1H), 7.58-7.41 (br m,2H), 7.37 (dd, J=8.1, 4.7 Hz, 1H), 7.17-7.08 (m, 2H), 4.62 (d, J=5.6 Hz,2H), 4.23 (t, J=6.2 Hz, 2H), 3.92 (br s, 2H), 2.98 (br s, 2H)

HPLCMS (Method C): [m/z]: 410.2 [M+H]⁺

1-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxamide(Example Compound No. 142)

In a similar fashion using general procedure 3,1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3,5-dimethyl-1H-pyrazole-4-carboxamidedihydrochloride (262) (150 mg, 0.384 mmol),1H-benzimidazole-2-carbaldehyde (73 mg, 0.499 mmol), DIPEA (0.268 ml,1.537 mmol) and MgSO₄ (100 mg) in MeOH (7 ml) at room temperature for 16h, followed by addition of NaBH₄ (22 mg, 0.576 mmol) gave the titlecompound (14 mg, 9%) as a yellow solid after purification by basicprep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.40-8.37 (m, 1H), 7.84(t, J=5.6 Hz, 1H), 7.72-7.66 (m, 1H), 7.56-7.50 (m, 1H), 7.46-7.42 (m,1H), 7.40 (dt, J=8.4, 4.4 Hz, 1H), 7.17-7.09 (m, 2H), 4.59 (d, J=4.3 Hz,2H), 4.05 (t, J=6.4 Hz, 2H), 3.92 (s, 2H), 2.90 (t, J=6.4 Hz, 2H), 2.38(s, 3H), 2.24 (s, 3H)

HPLCMS (Method D): [m/z]: 422.3 [M+H]⁺

1-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide(Example Compound No. 156)

In a similar fashion using general procedure 3,1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamidedihydrochloride (263) (81%, 100 mg, 0.20 mmol),1H-benzimidazole-2-carbaldehyde (35 mg, 0.24 mmol) and DIPEA (0.14 ml,0.8 mmol) in MeOH (5 ml) at room temperature for 16 h, followed byaddition of NaBH₄ (22 mg, 0.6 mmol) gave the title compound (12 mg, 13%)as a white solid after purification by basic prep-HPLC followed by flashcolumn chromatography (eluting with a gradient of 0-10% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.69 (t, 1H), 8.45 (s,1H), 8.37 (d, 1H), 7.72-7.66 (m, 1H), 7.53 (d, 1H), 7.45-7.38 (m, 2H),7.12 (t, 2H), 4.71-4.45 (m, 2H), 4.29 (t, 2H), 3.92 (s, 2H), 2.99 (s,2H)

HPLCMS (Method C): [m/z]: 462.1 [M+H]⁺

1-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamide(Example Compound No. 109)

In a similar fashion using general procedure 7,1-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1H-pyrazole-4-carboxamidedihydrochloride (258) (250 mg, 0.79 mmol),2-(2-chloroethyl)-1H-benzimidazole hydrochloride (340 mg, 1.58 mmol) andDIPEA (2.1 ml, 11.8 mmol) in DMF (7.5 ml) at room temperature for 6 d togive the title compound (17 mg, 5%) as a pale yellow solid afterpurification by prep-HPLC, followed by (KP—NH) flash columnchromatography using 4:6 EtOAc/heptane to 100% EtOAc then 20% MeOH: 80%DCM followed by prep-HPLC (MeCN/Water, 2 mM NH₄HCO₃).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.10 (s, 1H), 8.68 (t, J=6.0 Hz, 1H),8.50 (d, J=4.1 Hz, 1H), 8.21 (s, 1H), 7.90 (s, 1H), 7.74 (td, J=7.7, 1.8Hz, 1H), 7.58-7.33 (m, 2H), 7.29 (d, J=7.9 Hz, 1H), 7.25 (dd, J=7.4, 4.9Hz, 1H), 7.09 (dd, J=6.0, 2.8 Hz, 2H), 4.49 (d, J=6.0 Hz, 2H), 4.19 (t,J=6.2 Hz, 2H), 3.00-2.93 (m, 4H), 2.91 (t, J=6.2 Hz, 2H), 2.05 (s, 1H)

HPLCMS (Method B): [m/z]: 390.2 [M+H]⁺

1-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamidetetrahydrochloride (Example Compound No. 111)

In a similar fashion using general procedure 7,1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamidedihydrochloride (260) (0.7 g, 2.08 mmol),2-(2-chloroethyl)-1H-benzimidazole (0.451 g, 2.499 mmol) and DIPEA (5.4ml, 31.23 mmol) in DMF (15 ml) at 30° C. for 6 d gave the product as thefree base (63 mg) after purification by silica column chromatography(kp-NH, eluting with a gradient of 0-40% MeOH/EtOAc) followed by basicprep-HPLC. The freebase product was dissolved in MeOH (3 ml) and 12 MHCl (2 ml) at room temperature for 2 h to give the title compound (65mg, 5.6%) as a brown solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.46 (s, 1H), 8.25 (s, 1H), 8.01(s, 1H), 7.81 (dd, J=6.2, 3.2 Hz, 3H), 7.63 (dd, J=6.2, 3.1 Hz, 3H),4.78 (s, 2H), 4.64 (s, 2H), 3.72 (d, J=7.6 Hz, 6H)

HPLCMS (Method B): [m/z]: 408.2 [M+H]⁺

1-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamidetrihydrochioride (Example Compound No. 131)

In a similar fashion using general procedure 7,1-(2-aminoethyl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamidedihydrochloride (259) (0.2 g, 0.51 mmol),2-(2-chloroethyl)-1H-benzimidazole hydrochloride (0.13 g, 0.61 mmol) andDIPEA (0.44 ml, 2.55 mmol) in DMF (3 ml) at room temperature for 72 hthen heated to 40° C. for 21 h gave the free base product (55 mg) afterpurification basic prep-HPLC. The free base product was then dissolvedin MeOH (3 ml) and 12 M HCl (0.5 ml) at room temperature for 2 h to givethe title compound (0.049 g, 18%) as a brown solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.60 (d, J=5.2 Hz, 1H), 8.51 (d,J=6.8 Hz, 1H), 8.31 (s, 1H), 8.03 (s, 1H), 7.95-7.91 (m, 1H), 7.83-7.79(m, 2H), 7.65-7.62 (m, 2H), 5.80 (t, J=8.5 Hz, 1H), 4.68-4.64 (m, 2H),3.77-3.70 (m, 6H), 3.34 (d, J=3.3 Hz, 1H), 3.23-3.17 (m, 1H), 2.83-2.75(m, 1H), 2.39-2.30 (m, 1H)

HPLCMS (Method B): [m/z]: 416.1 [M+H]⁺

1-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(Example Compound No. 144)

In a similar fashion using general procedure 7,1-(2-aminoethyl)-N-[(3-chloropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamidedihydrochloride (261) (0.45 g, 1.28 mmol),2-(2-chloroethyl)-1H-benzimidazole (0.28 g, 1.53 mmol) and DIPEA (3.3ml, 19.14 mmol) in DMF (7 ml) at room temperature for 66 h, then heatedto 40° C. for 90 h, gave the title compound (112 mg, 21%) as acolourless film after purification by flash column chromatography(kp-NH, eluting with a gradient of 0-10% MeOH/DCM) followed by basicprep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.10 (s, 1H), 8.52-8.44 (m, 2H), 8.22(s, 1H), 7.92 (dd, J=8.1, 1.4 Hz, 1H), 7.90 (s, 1H), 7.55-7.38 (br m,2H), 7.37 (dd, J=8.1, 4.7 Hz, 1H), 7.13-7.07 (m, 2H), 4.63 (d, J=5.7 Hz,2H), 4.20 (t, J=6.2 Hz, 2H), 2.99-2.93 (m, 4H), 2.93-2.89 (m, 2H)

HPLCMS (Method C): [m/z]: 424.1 [M+H]⁺

1-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide(Example Compound No. 162)

In a similar fashion using general procedure 8, DBU (62.94 μl, 0.42mmol),1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-3-(trifluoromethyl)-1H-pyrazole-4-carboxamidedihydrochloride (263) (81%, 140 mg, 0.28 mmol) andN-(2-nitrophenyl)prop-2-enamide (D) (52.84 mg, 0.27 mmol) in MeCN (5 ml)at room temperature for 16 h gave a residue (0.160 g) as a mixture ofmono:bis-alkylated (1:1) adducts. The residue was dissolved in AcOH (4ml). Iron (0.03 g) was added and the reaction heated to 80° C. for 1 h.The reaction was cooled and diluted with water (5 ml). The mixture wascooled in an ice-bath and basified to pH 12 using 10 M NaOH. Water (10ml) was added and the mixture extracted with CHCl₃:IPA (4:1, 4×30 ml).The combined organic layers were dried (Na₂SO₄), filtered andevaporated. Purification by flash column chromatography (eluting with agradient 5-10% MeOH/DCM followed by 0-10% 7 N NH₃ in MeOH/DCM) followedby purification by basic prep-HPLC gave the title compound (19 mg,13.9%) as a colourless oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.11 (br s, 1H), 8.69 (t, J=5.6 Hz,1H), 8.43 (s, 1H), 8.42-8.35 (m, 1H), 7.74-7.65 (m, 1H), 7.52-7.36 (brm, 2H), 7.43-7.37 (m, 1H), 7.15-7.06 (br m, 2H), 4.59-4.55 (m, 2H), 4.26(t, J=6.1 Hz, 2H), 3.02-2.94 (m, 4H), 2.94-2.89 (m, 2H)

HPLCMS (Method C): [m/z]: 476.2 [M+H]⁺

Ethyl 1-[2-(benzyloxy)-2-oxoethyl]-1H-pyrazole-4-carboxylate (268)

Benzyl bromoacetate (2.82 ml, 18 mmol) was added dropwise to an ice-coldsuspension of ethyl 1H-pyrazole-4-carboxylate (2.3 g, 16 mmol) andK₂COO₃ (3.4 g, 25 mmol) in DMF (20 ml). The mixture was warmed to roomtemperature and stirred for 2 h. The mixture was diluted with diethylether (100 ml) and washed with water (2×40 ml) and brine (5×20 ml). Theorganic phase was dried (Na₂SO₄), filtered and evaporated in vacuo.Purification by flash chromatography using an elution gradient 0-100%DCM/heptane afforded the title compound (1.57 g, 33%) as a colourlessoil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.01 (s, 1H), 7.98 (s, 1H), 7.44-7.32(m, 5H), 5.24 (s, 2H), 4.98 (s, 2H), 4.32 (q, J=7.1 Hz, 2H), 1.37 (t,J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 288.95 [M+H]⁺

2-[4-(Ethoxycarbonyl)-1H-pyrazol-1-yl]acetic acid (269)

A suspension of ethyl1-[2-(benzyloxy)-2-oxoethyl]-1H-pyrazole-4-carboxylate (268) (1.57 g,5.44 mmol) and palladium on carbon (10% wt, 0.590 g, 0.55 mol) in EtOH(50 ml) was stirred under an atmosphere of hydrogen for 2.5 h. Themixture was filtered through a plug of Celite and the residue rinsedwith MeOH. The combined filtrates were evaporated in vacuo to give thetitle compound (0.99 mg, 92%) as a yellow solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.07 (s, 1H), 8.03 (s, 1H), 5.07 (s,2H), 4.34 (q, J=7.1 Hz, 2H), 1.37 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 198.9 [M+H]⁺

Ethyl1-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]carbamoyl}methyl)-1H-pyrazole-4-carboxylate(270)

In a similar fashion to general procedure 6, HATU (1.1 g, 2.88 mmol),2-[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]acetic acid (269) (0.476 g, 2.4mmol), 2-(1H-1,3-benzodiazol-2-yl)ethan-1-amine dihydrochloride (0.62 g,2.64 mmol) and DIPEA (1.67 ml, 9.61 mmol) in THF (30 ml) at roomtemperature for 2 h afforded the title compound (0.676 g, 82%) as awhite solid after purification by flash chromatography (eluting with agradient elution 0-8% MeOH/DCM).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.01 (s, 1H), 7.87 (s, 1H), 7.62 (m,2H), 7.36 (m, 3H), 4.90 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.80 (q, J=5.9Hz, 3H), 3.39 (t, J=5.9 Hz, 2H), 1.34 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 342.1 [M+H]⁺

1-({[2-(1H-1,3-Benzodiazol-2-yl)ethyl]carbamoyl}methyl)-1H-pyrazole-4-carboxylicacid (271)

In a similar fashion to general procedure 5, ethyl1-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]carbamoyl}methyl)-1H-pyrazole-4-carboxylate(270) (667 mg, 1.95 mmol) and LiOH (140 mg, 5.85 mmol) in THF/water (30ml/4 ml) at room temperature for 16 h, gave the crude title compound(420 mg) as a white residue.

HPLCMS (Method A): [m/z]: 314 [M+H]⁺

1-({[2-(1H-1,3-Benzodiazol-2-yl)ethyl]carbamoyl}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamidedihydrochloride (Example Compound No. 117)

In a similar fashion to general procedure 6, crude1-({[2-(1H-1,3-benzodiazol-2-yl)ethyl]carbamoyl}methyl)-1H-pyrazole-4-carboxylicacid (271) (200 mg), (3-fluoropyridin-2-yl)methanamine dihydrochloride(A2) (140 mg, 0.7 mmol), DIPEA (0.44 ml, 2.55 mmol) and HATU (290 mg,0.76 mmol) in THF (10 ml) and DMF (2 ml) afforded the title compound asthe freebase after purification by flash column chromatography (elutingwith a gradient of 0-20% MeOH/DCM) followed by basic prep-HPLC. Thefreebase was converted to the di HCl salt (28 mg, 9%) after treatmentwith 12M HCl (1 ml) in MeOH (5 ml).

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.49 (d, J=5.2 Hz, 1H), 8.13 (s,1H), 8.00-7.92 (m, 2H), 7.76 (dt, J=6.7, 3.4 Hz, 2H), 7.67 (dt, J=8.8,4.8 Hz, 1H), 7.59 (dt, J=6.2, 3.4 Hz, 2H), 4.88 (s, 2H), 4.79 (d, J=1.4Hz, 2H), 3.77 (t, J=6.4 Hz, 2H), 3.39 (t, J=6.4 Hz, 2H)

HPLCMS (Method C): [m/z]: 422.2 [M+H]⁺

General Scheme 15 Above1-{1-[(Tert-butoxy)carbonyl]piperidin-4-yl}-1H-pyrazole-4-carboxylicacid (272)

Ethyl 1H-pyrazole-4-carboxylate (0.2 g, 1.427 mmol), tert-butyl4-[(methylsulfonyl)oxy]piperidine-1-carboxylate (0.362 g, 1.296 mmol) inDMF (5 ml) were stirred for 5 min. The reaction was cooled to 00 and NaH(0.234 g, 5.85 mmol) added portion wise. Once gas evolution ceased, thereaction was heated to 50° C. for 26 h. The reaction was cooled,quenched with water (15 ml) and evaporated to dryness. Water (40 ml) wasadded and the aqueous layer extracted with EtOAc (3×15 ml). The aqueouslayer was acidified with saturated KHSO₄ to pH 3 and extracted withEtOAc (4×20 ml). The combined organic layers were dried (MgSO₄),filtered and evaporated to give the title compound (0.331 g, 79%) as apale yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.29 (s, 1H), 7.81 (s, 1H), 4.44-4.36(m, 1H), 4.08-3.97 (m, 2H), 2.89 (s, 2H), 2.01-1.95 (m, 2H), 1.79 (qd,J=12.4, 4.4 Hz, 2H), 1.41 (s, 9H)

HPLCMS (Method A): [m/z]: 318.0 [M+Na]⁺

Tert-butyl4-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate(273)

In a similar fashion using general procedure 6,1-{1-[(tert-butoxy)carbonyl]piperidin-4-yl}-1H-pyrazole-4-carboxylicacid (272) (301 mg, 1.02 mmol), 3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (358 mg, 1.53 mmol), DIPEA (0.8 ml), HATU (581 mg,1.53 mmol) in THF (15 ml) and DMF (3 ml) gave the title compounds (315mg, 65%) as a glassy solid after purification by flash columnchromatography (eluting with a gradient of 20-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.51 (t, J=5.7 Hz, 1H), 8.37 (dt,J=4.6 and 1.5 Hz, 1H), 8.25 (s, 1H), 7.89 (s, 1H), 7.71-7.64 (m, 1H),7.42-7.36 (m, 1H), 4.57 (dd, J=5.7, 1.5 Hz, 2H), 4.44-4.32 (m, 1H),4.04-3.96 (m, 2H), 2.89 (br s, 2H), 2.01 (s, 2H), 1.74 (qd, J=12.4, 4.4Hz, 2H), 1.41 (s, 9H)

HPLCMS (Method A): [m/z]: 404.1 [M+H]⁺

N-[(3-Fluoropyridin-2-yl)methyl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamidedihydrochloride (274)

In a similar fashion using general procedure 2, 12M HCl (1.1 ml) andtert-butyl4-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)piperidine-1-carboxylate(273) (315 mg, 0.664 mmol) in MeOH (4 ml) at 3500 for 16 h gave thetitle compound (277 mg) as an off-white solid. The compound was used inthe next step without further purification.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.54-8.47 (m, 1H), 8.22 (d, J=2.4Hz, 1H), 8.00-8.11 (m, 1H), 7.98 (s, 1H), 7.69-7.78 (m, 1H), 4.80 (s,2H), 4.66-4.56 (m, 1H), 3.56 (dt, J=13.1, 3.4 Hz, 2H), 3.22 (td, J=12.8,3.4 Hz, 2H), 2.38-2.19 (m, 4H)

HPLCMS (Method A): [m/z]: 304 [M+H]⁺

1-[1-(1H-1,3-Benzodiazol-2-ylmethyl)piperidin-4-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide (Example Compound No. 150)

In a similar fashion to general procedure 7,2-(Chloromethyl)-1H-benzimidazole (71 mg, 0.424 mmol),N-[(3-fluoropyridin-2-yl)methyl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamide(274) (99 mg, 0.326 mmol) and DIPEA (0.171 ml, 0.98 mmol) in DMF (2 ml)at 30° C. for 16 h, gave the title compound (21 mg, 15%) as a whitesolid after purification by basic prep-HPLC followed by furtherpurification by flash column chromatography (kp-NH, eluting with agradient of 0-20% MeOH/EtOAc).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.28 (s, 1H), 8.52 (t, J=5.7 Hz, 1H),8.37 (dt, J=4.6, 1.5 Hz, 1H), 8.22 (s, 1H), 7.89 (s, 1H), 7.71-7.65 (m,1H), 7.54 (br s, 1H), 7.44 (br s, 1H), 7.42-7.36 (m, 1H), 7.14 (br s,2H), 4.58 (dd, J=5.7, 1.6 Hz, 2H), 4.26-4.12 (m, 1H), 3.77 (s, 2H), 2.95(d, J=12.0 Hz, 2H), 2.32-2.23 (m, 2H), 2.05-1.94 (m, 4H)

HPLCMS (Method D): [m/z]: 434.3 [M+H]⁺

1-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]piperidin-4-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(Example Compound No. 198)

In a similar fashion to general procedure 8, DBU (0.28 ml, 1.89 mmol),N-[(3-fluoropyridin-2-yl)methyl]-1-(piperidin-4-yl)-1H-pyrazole-4-carboxamidedihydrochloride (274) (248 mg, 0.47 mmol) andN-(2-nitrophenyl)prop-2-enamide (D) (154 mg, 0.8 mmol) in MeCN (10 ml)at room temperature for 17 h gave the required intermediate (200 mg,82%) after purified by flash column chromatography (eluting with agradient of 0-25% MeOH/EtOAc) to give the title compound as a yellowsolid.

HPLCMS (Method A): [m/z]: 496.1 [M+H]⁺

The intermediate was further treated with iron powder (87 mg, 1.56 mmol)in AcOH (3 ml) at 80° C. for 1.5 h, to give the title compound (72 mg,33%) as an off-white solid after purification by flash columnchromatography eluting with 0 to 20% MeOH/DCM.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.51 (t, J=5.7 Hz, 1H),8.38 (dt, J=4.6, 1.5 Hz, 1H), 8.24 (s, 1H), 7.89 (s, 1H), 7.72-7.65 (m,1H), 7.51 (s, 1H), 7.46-7.37 (m, 2H), 7.11 (d, J=5.1 Hz, 2H), 4.58 (dd,J=5.7, 1.6 Hz, 2H), 4.22-4.12 (m, 1H), 3.07-2.96 (m, 4H), 2.82 (t, J=7.5Hz, 2H), 2.23-2.14 (m, 2H), 2.05-1.97 (m, 2H), 1.95-1.86 (m, 2H)

HPLCMS (Method C): [m/z]: 448.3 [M+H]⁺

Tert-butyl3-{[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxylate(275)

Ethyl 1H-pyrazole-4-carboxylate (334 mg, 2.38 mmol), tert-butyl3-(hydroxymethyl)piperidine-1-carboxylate (667 mg, 3.1 mmol) andtriphenylphosphine (1.25 g, 4.8 mmol) were dissolved in THF (30 ml) andcooled in an ice-water bath. DIAD (0.94 ml, 4.8 mmol) was addeddropwise. The mixture was stirred whilst warming to room temperature for18 h. The reaction mixture was diluted with ethyl acetate (80 ml) andwashed with sat. NaHCO₃ (aq) (50 ml) and brine (50 ml). The organicphase was dried (Na₂SO₄), filtered and evaporated in vacuo. Purificationby flash chromatography using a gradient elution of 0-40% EtOAc/heptanegave the crude title compound (2.23 g) as a colourless oil. The crudeproduct was used in the next step without further purification.

HPLCMS (Method A): [m/z]: 338.15 [M+H]⁺

1-({1-[(Tert-butoxy)carbonyl]piperidin-3-yl}methyl)-1H-pyrazole-4-carboxylicacid (276)

In a similar fashion using general procedure 5, tert-butyl3-{[4-(ethoxycarbonyl)-1H-pyrazol-1-yl]methyl}piperidine-1-carboxylate(275) (2.23 g, 4.69 mmol, 71% purity) and LiOH (1.12 g, 0.05 mol) inTHF/water (20 ml/20 ml) gave the crude product (638 mg, 16%, 38% purity)as a colourless oil.

HPLCMS (Method A): [m/z]: 310.05 [M+H]⁺

Tert-butyl3-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylate(277)

In a similar fashion using general procedure 6,1-({1-[(tert-butoxy)carbonyl]piperidin-3-yl}methyl)-1H-pyrazole-4-carboxylicacid (276) (0.638 g, 2.06 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.451 g, 2.27 mmol), DIPEA (1.26 ml, 7.2 mmol) andHATU (1.18 g, 3.1 mmol) in THF (40 ml) and DMF (5 ml) gave the crudetitle compound (0.348 g, 32%, 79% purity) as a hygroscopic yellow solidafter purification by flash column chromatography (eluting with agradient of 0-100% EtOAc/heptane followed by 4-8% MeOH/EtOAc).

HPLCMS (Method A): [m/z]: 418.15 [M+H]⁺

N-[(3-Fluoropyridin-2-yl)methyl]-1-(piperidin-3-ylmethyl)-1H-pyrazole-4-carboxamide(278)

In a similar fashion using general procedure 2, tert-butyl3-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)methyl]piperidine-1-carboxylate(277) (348 mg, 0.83 mmol) and 12 M HCl (0.69 ml) gave the title compound(182 mg, 64%) as the free base after purification using an SCX-2cartridge, rinsing with DCM and MeOH, then elution with 7 N ammonia inMeOH.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.36 (dt, J=4.7, 1.1 Hz, 1H), 8.18(s, 1H), 7.97 (s, 1H), 7.60 (ddd, J=9.8, 8.4, 1.2 Hz, 1H), 7.39 (dt,J=8.6, 4.4 Hz, 1H), 4.73 (d, J=1.5 Hz, 2H), 4.18 (td, J=7.1, 2.6 Hz,2H), 3.29-3.22 (m, 1H), 3.19-3.13 (m, 1H), 2.81 (td, J=12.5, 3.1 Hz,1H), 2.70 (t, J=12.1 Hz, 1H), 2.42-2.30 (m, 1H), 1.94-1.85 (m, 1H),1.83-1.66 (m, 2H), 1.35-1.22 (m, 1H)

HPLCMS (Method A): [m/z]: 318.10 [M+H]⁺

1-{[1-(1H-1,3-Benzodiazol-2-ylmethyl)piperidin-3-y]methyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(Example Compound No. 153)

In a similar fashion using general procedure 7,N-[(3-fluoropyridin-2-yl)methyl]-1-(piperidin-3-ylmethyl)-1H-pyrazole-4-carboxamide(278) (180 mg, 0.57 mmol), 2-(chloromethyl)-1H-1,3-benzodiazole (189 mg,1.13 mmol) and DIPEA (180 mg, 1.4 mmol) in DMF (8 ml) gave the titlecompound (66 mg, 25%) after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.20 (s, 1H), 8.54 (t, J=5.7 Hz, 1H),8.37 (dt, J=4.6, 1.2 Hz, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 7.71-7.65 (m,1H), 7.53 (d, J=7.4 Hz, 1H), 7.45-7.36 (m, 2H), 7.18-7.07 (m, 2H), 5.75(s, OH), 4.60-4.54 (m, 2H), 4.12-3.99 (m, 2H), 3.67 (q, J=14.0 Hz, 2H),2.71-2.62 (m, 3H), 2.17-2.04 (m, 2H), 1.96 (t, J=10.4 Hz, 1H), 1.67-1.58(m, 1H), 1.54-1.38 (m, 2H), 1.05-0.91 (m, 1H)

HPLCMS (Method C): [m/z]: 448.3 [M+H]⁺

Ethyl1-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}methyl)-1H-pyrazole-4-carboxylate(279)

Ethyl 1H-pyrazole-4-carboxylate (0.55 g, 3.92 mmol), tert-butyl3-(bromomethyl)azetidine-1-carboxylate (0.982 g, 3.92 mmol) andpotassium carbonate (1.08 g, 8 mmol) in DMF (10 ml) were stirred at roomtemperature for 16 h. The mixture was diluted with water and extractedwith EtOAc (3×50 ml). The combined organic extracts were washed withbrine (4×50 ml), dried (Na₂SO₄), filtered and evaporated in vacuo toyield the title compound (1.33 g) as a pale yellow oil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=7.92 (s, 1H), 7.90 (s, 1H), 4.38-4.26(m, 4H), 4.06 (t, J=9.0 Hz, 2H), 3.74 (dd, J=9.0, 5.1 Hz, 2H), 3.17-3.01(m, 1H), 1.46 (s, 9H), 1.37 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 310.15 [M+H]⁺

1-({1-[(Tert-butoxy)carbonyl]azetidin-3-yl}methyl)-1H-pyrazole-4-carboxylicacid (280)

In a similar fashion using general procedure 5, LiOH (2.06 g, 86 mmol)and ethyl1-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}methyl)-1H-pyrazole-4-carboxylate(279) (1.33 g, 4.3 mmol) in THF (30 ml) and water (30 ml) gave the titlecompound (1.02 g, 83%) as a white solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=12.31 (s, 1H), 8.31 (s, 1H), 7.81 (s,1H), 4.36 (d, J=7.3 Hz, 2H), 3.94-3.81 (m, 2H), 3.72-3.61 (m, 2H),3.07-2.89 (m, 1H), 1.37 (s, 9H)

HPLCMS (Method A): [m/z]: 304.05 [M+Na]⁺

Tert-butyl3-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)methyl]azetidine-1-carboxylate(281)

In a similar fashion using general procedure 6,1-({1-[(tert-butoxy)carbonyl]azetidin-3-yl}methyl)-1H-pyrazole-4-carboxylicacid (280) (500 mg, 1.78 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (389 mg, 1.96 mmol), DIPEA (1.1 ml, 6 mmol) andHATU (740 mg, 2 mmol) in DCM (30 ml) gave the title compound (624 mg,89%) as a colourless oil after purification by flash columnchromatography using a gradient elution of 50 to 100% EtOAc/heptanefollowed by 0 to 10% MeOH/EtOAc.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.32 (dt, J=4.7, 1.1 Hz, 1H), 7.84 (s,1H), 7.79 (s, 1H), 7.35 (m, 1H), 7.24-7.20 (m, 1H), 4.71 (dd, J=4.5, 1.3Hz, 2H), 4.27 (d, J=7.6 Hz, 2H), 3.97 (t, J=8.6 Hz, 2H), 3.66 (dt,J=7.6, 3.9 Hz, 2H), 3.02-2.98 (m, 1H), 1.36 (s, 9H)

HPLCMS (Method A): [m/z]: 390.1 [M+H]⁺

1-(Azetidin-3-ylmethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(282)

In a similar fashion using general procedure 2, tert-butyl3-[(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1H-pyrazol-1-yl)methyl]azetidine-1-carboxylate(281) (624 mg, 1.6 mmol) and 12 M HCl (2 ml) in MeOH (20 ml) gave thefree base title compound (248 mg, 54%) as a white solid afterpurification using an SCX-2 cartridge, rinsing with DCM and MeOH, thenelution with 7 N ammonia in MeOH.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.42 (d, J=4.6 Hz, 1H), 7.94 (s, 1H),7.88 (s, 1H), 7.44 (t, J=9.3 Hz, 1H), 7.34-7.25 (m, 1H), 4.81 (d, J=4.2Hz, 2H), 4.42 (d, J=7.4 Hz, 2H), 3.82 (t, J=8.2 Hz, 2H), 3.55-3.47 (m,2H), 3.28 (m, 1H)

HPLCMS (Method A): [m/z]: 290 [M+H]⁺

1-{[1-(1H-1,3-Benzodiazol-2-ylmethyl)azetidin-3-yl]methyl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(Example Compound No. 187)

In a similar fashion using general procedure 3,1-(azetidin-3-ylmethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(281) (50 mg, 0.17 mmol), 1H-benzimidazole-2-carbaldehyde (37.9 mg, 0.26mmol), DIPEA (0.06 ml, 0.34 mmol) and MgSO₄ (300 mg) in MeOH (5 ml) atroom temperature for 18 h, followed by addition of NaBH₄ (7 mg, 0.17mmol) afforded the title compound (32 mg, 43%) as pale yellow solidafter purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.08 (s, 1H), 8.54 (t, J=5.7 Hz, 1H),8.37 (dt, J=4.6, 1.4 Hz, 1H), 8.18 (s, 1H), 7.87 (s, 1H), 7.68 (ddd,J=10.1, 8.3, 1.3 Hz, 1H), 7.47 (s, 2H), 7.40 (dt, J=8.6, 4.4 Hz, 1H),7.15-7.10 (m, 2H), 4.57 (dd, J=5.6, 1.5 Hz, 2H), 4.35 (d, J=7.5 Hz, 2H),3.77 (s, 2H), 3.38 (t, J=7.5 Hz, 2H), 3.12-3.05 (m, 2H), 2.89-2.79 (m,1H)

HPLCMS (Method C): [m/z]: 420.1 [M+H]⁺

1-({1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]azetidin-3-yl}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide[Example Compound No. 192]

In a similar fashion using general procedure 8,1-(azetidin-3-ylmethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(281) (200 mg, 0.69 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (139.5mg, 0.73 mmol) and DBU (0.12 ml, 0.83 mmol) in MeCN (10 ml) gave thecrude intermediate which was further reacted with iron powder (130 mg)in AcOH (3 ml). Purification by basic prep-HPLC followed by flash columnchromatography (eluting with a gradient of 0-20% MeOH/DCM) gave thetitle compound (67 mg, 25%) as a white solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.36 (dt, J=4.5, 1.3 Hz, 1H), 8.12(s, 1H), 7.93 (s, 1H), 7.61 (ddd, J=9.8, 8.5, 1.3 Hz, 1H), 7.52 (td,J=6.1, 3.1 Hz, 2H), 7.40 (dt, J=8.5, 4.5 Hz, 1H), 7.24-7.17 (m, 2H),4.73 (d, J=1.6 Hz, 2H), 4.37 (d, J=7.2 Hz, 2H), 3.45 (t, J=7.9 Hz, 2H),3.14-3.07 (m, 2H), 3.00 (dq, J=13.8, 7.0 Hz, 1H), 2.94 (s, 4H)

HPLCMS (Method C): [m/z]: 434.2 [M+H]⁺

General Scheme 16 Above Methyl 1H-pyrazole-4-carboxylate (282)

1H-pyrazole-4-carboxylic acid (20 g, 178.4 mmol) and sulfuric acid(39.65 ml) in MeOH (200 ml) were heated at 70° C. for 20 h. The reactionmixture was cooled to room temperature and concentrated in vacuo.Aqueous NaOH solution was added to adjust the pH to 6. The aqueous layerwas extracted with EtOAc (3×200 ml) and the combined organic extractswere dried (MgSO₄), filtered and evaporated in vacuo to afford the titlecompound (18.5 g, 78%) as a white solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.10 (s, 2H), 3.87 (s, 3H)

HPLCMS (Method A): [m/z]: 126.85 [M+H]⁺

Methyl 1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylate(283)

A suspension of methyl 1H-pyrazole-4-carboxylate (282) (3.34 g, 26.48mmol), 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (10.93 g, 34.43mmol) and potassium carbonate (10.98 g, 79 mmol) in DMF (70 ml) washeated at 100° C. for 3 h. The reaction mixture was cooled to roomtemperature and diluted with water (150 ml). The mixture was extractedwith EtOAc (3×150 ml), the combined organic extracts were washed withbrine (5×100 ml), dried (Na₂SO₄), filtered and evaporated in vacuo. Theresidue was flushed through a plug of silica (15 g) (eluting with 10-20%EtOAc/heptane), the eluent was evaporated in vacuo and the titlecompound (4.03 g, 44%) obtained as a white solid after precipitationfrom EtOAc/heptane.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.14 (s, 1H), 7.96 (s, 1H), 7.49-7.42(m, 4H), 7.36-7.17 (m, 6H), 4.98 (m, 1H), 4.54 (s, 1H), 3.86 (s, 3H),3.75-3.69 (td, J=7.2, 1.5 Hz, 2H), 3.54-3.45 (m, 2H)

HPLCMS (Method A): [m/z]: 348.10 [M+H]⁺

1-[1-(Diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylic acid (284)

In a similar fashion to general procedure 5, methyl1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylate (283) (2.1g, 6.04 mmol) and LiOH (1.45 g, 60 mmol) in THF/water (20 ml/20 ml)afforded the title compound (1.95 g, 93%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.15 (s, 1H), 8.04 (s, 1H), 7.82-7.70(m, 4H), 7.51-7.37 (m, 6H), 5.65-5.55 (m, 1H), 5.55-5.42 (m, 1H),4.84-4.69 (m, 2H), 4.39-4.25 (m, 2H)

HPLCMS (Method A): [m/z]: 334.1 [M+H]⁺

1-[1-(Diphenylmethyl)azetidin-3-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(285)

In a similar fashion to general procedure 6,1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylic acid (284)(1.18 g, 2.46 mmol), (3-fluoropyridin-2-yl)methanamine dihydrochloride(A2) (0.587 g, 2.95 mmol), DIPEA (1.71 ml, 9.82 mmol) and HATU (1.21 g,3.19 mmol) in THF (50 ml) and DMF (10 ml) afforded the title compound(1.06 g, 82%) as a yellow solid after purification by flash columnchromatography (eluting with a gradient of 60-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.59 (t, J=5.7 Hz, 1H), 8.40 (s, 1H),8.37 (d, J=4.6 Hz, 1H), 7.93 (s, 1H), 7.68 (t, J=9.3 Hz, 1H), 7.47 (m,4H), 7.39 (m, 1H), 7.29 (t, J=7.6 Hz, 4H), 7.19 (t, J=7.3 Hz, 2H), 5.04(p, J=6.8 Hz, 1H), 4.62-4.56 (m, 3H), 3.59 (t, J=7.7 Hz, 2H), 3.35 (s,2H)

HPLCMS (Method A): [m/z]: 442.15 [M+H]⁺

N-{5H,6H,7H-Cyclopenta[b]pyridin-7-yl}-1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxamide(286)

In a similar fashion to general procedure 61-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxylic acid (284)(500 mg, 1.5 mmol), 5H,6H,7H-cyclopenta[b]pyridin-7-aminedihydrochloride (404 mg, 1.95 mmol), DIPEA (0.86 ml, 5 mmol) and HATU(0.74 g, 2 mmol) in DCM (20 ml) afforded the crude title compound (949mg) as a white residue which was used in the next step without furtherpurification.

HPLCMS (Method A): [m/z]: 450.15 [M+H]⁺

1-(Azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(287)

1-[1-(diphenylmethyl)azetidin-3-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(285) (1.06 g, 2.01 mmol) and Pd/C (10%) (0.20 g, 0.201 mmol) weresuspended in EtOH (11 ml). A solution of TEA (0.849 ml, 6.04 mmol) andformic acid (0.228 ml, 6.04 mmol) in EtOH (11 ml) was added and thereaction mixture was stirred at reflux for 2 h. The mixture was cooledto room temperature, filtered through a plug of Celite and the residuerinsed with MeOH (10 ml). The filtrate was evaporated in vacuo to affordthe crude material. Purification using a SCX-2 cartridge, washing withDCM and MeOH and eluting with 7 N ammonia/MeOH gave the title compound(0.354 g, 56%) as a colourless oil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.57 (t, J=5.6 Hz, 1H), 8.37 (d, J=4.6Hz, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.72-7.65 (m, 1H), 7.40 (dd, J=8.5,4.3 Hz, 1H), 5.18 (p, J=7.3 Hz, 1H), 4.58 (dd, J=5.6, 1.4 Hz, 2H), 3.84(t, J=7.7 Hz, 2H), 3.73 (t, J=8.1 Hz, 2H)

HPLCMS (Method A): [m/z]: 276.1 [M+H]⁺

1-(Azetidin-3-yl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamide(288)

CrudeN-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1-[1-(diphenylmethyl)azetidin-3-yl]-1H-pyrazole-4-carboxamide(286) (949 mg) and palladium (10% wt. on carbon, 0.12 g, 0.11 mmol) weresuspended in EtOH (20 ml). TEA (454 μL, 3 mmol) and formic acid (125 μL,3 mmol) in EtOH (20 ml) were added and the mixture heated at reflux for1 h. The reaction mixture was cooled to room temperature and filteredthrough a plug of Celite. The residue was rinsed with MeOH and thecombined filtrates evaporated in vacuo. The residue was dissolved in aminimum amount of MeOH and purified by passage through an SCX-2cartridge, rinsing with DCM and MeOH and elution with 7 N ammonia inMeOH. Evaporation of the basic eluent afforded the title compound (342mg, quant) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.40-8.34 (m, 3H), 7.94 (s, 1H), 7.68(d, J=7.6 Hz, 1H), 7.22 (dd, J=7.6, 4.9 Hz, 1H), 5.48-5.40 (m, 1H), 5.18(m, 1H), 3.88-3.81 (m, 2H), 3.78-3.71 (m, 2H), 2.98 (ddd, J=16.0, 8.9,3.0 Hz, 1H), 2.86 (dt, J=16.0, 8.3 Hz, 2H), 2.47 (dd, J=6.5, 4.8 Hz,1H), 1.95-1.84 (m, 1H)

HPLCMS (Method A): [m/z]: 284.05 [M+H]⁺

1-[1-(1H-1,3-Benzodiazol-2-ylmethyl)azetidin-3-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide[Example Compound No. 136]

In a similar fashion using general procedure 3,1-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(287) (196 mg, 0.71 mmol), 1H-1,3-benzodiazole-2-carbaldehyde (125 mg,0.85 mmol) and MgSO₄ (100 mg) in MeOH (8 ml) at room temperature for 3d, followed by addition of NaBH₄ (81 mg, 2.1 mmol) afforded the titlecompound (82 mg, 28%) as a white solid after purification by basicprep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.32 (s, 1H), 8.58 (t, J=5.7 Hz, 1H),8.43 (s, 1H), 8.39-8.37 (m, 1H), 7.96 (s, 1H), 7.69 (ddd, J=10.0, 8.3,1.2 Hz, 1H), 7.61-7.45 (m, 2H), 7.40 (dt, J=8.6, 4.4 Hz, 1H), 7.17-7.10(m, 2H), 5.06 (m, 1H), 4.59 (dd, J=5.7, 1.5 Hz, 2H), 3.92 (s, 2H),3.85-3.81 (m, 2H), 3.61-3.57 (m, 2H)

HPLCMS (Method C): [m/z]: 406.2 [M+H]⁺

1-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(Example Compound No. 167)

In a similar fashion to general procedure 8,1-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1H-pyrazole-4-carboxamide(287) (364 mg, 1.32 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (254 mg,1.32 mmol) and DBU (0.197 ml, 1.32 mmol) in MeCN (12 ml) gave the crudeintermediate which was following treatment with AcOH (8 ml) and ironpowder (62 mg) gave the title compound (104 mg, 43%) as a white solidafter purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.15 (s, 1H), 8.56 (t, J=5.7 Hz, 1H),8.37 (d, J=4.6 Hz, 1H), 8.34 (s, 1H), 7.93 (s, 1H), 7.71-7.65 (m, 1H),7.49 (br s, 1H), 7.45-7.37 (m, 2H), 7.14-7.07 (m, 2H), 4.98 (p, J=6.8Hz, 1H), 4.59-4.56 (m, 2H), 3.69 (t, J=7.6 Hz, 2H), 3.38 (t, J=7.3 Hz,2H), 2.94 (t, J=7.1 Hz, 2H), 2.85 (t, J=7.0 Hz, 2H)

HPLCMS (Method D): [m/z]: 420.3 [M+H]⁺

1-{1-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamide(Example Compound No. 191)

In a similar fashion to general procedure 8,1-(azetidin-3-yl)-N-{5H,6H,7H-cyclopenta[b]pyridin-7-yl}-1H-pyrazole-4-carboxamide(288) (342 mg, 1.21 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (244 mg,1.27 mmol) and DBU (0.22 ml, 1.5 mmol) in MeCN (10 ml) afforded a crudeintermediate which was further reacted with iron powder (170 mg, 3 mmol)in AcOH (4 ml) to afford the title compound (145 mg, 44%) as a whitesolid after purification by basic prep-HPLC followed by flash columnchromatography (eluting with a gradient of 0-20% MeOH/DCM).

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=8.37 (d, J=5.0 Hz, 1H), 8.26 (s,1H), 8.01 (s, 1H), 7.78-7.73 (m, 1H), 7.52 (dd, J=5.4, 3.0 Hz, 2H), 7.30(dd, J=7.6, 5.0 Hz, 1H), 7.24-7.18 (m, 2H), 5.56 (t, J=8.2 Hz, 1H), 5.06(m, 1H), 3.86 (td, J=7.3, 1.6 Hz, 2H), 3.64-3.58 (m, 2H), 3.11-3.07 (m,3H), 3.03-2.92 (m, 3H), 2.69 (m, 1H), 2.02 (m, 1H)

HPLCMS (Method C): [m/z]: 428.2 [M+H]⁺

General Scheme 18 Above Tert-butyl2-(cyanomethyl)-1H-1,3-benzodiazole-1-carboxylate (296)

2-(1H-1,3-benzodiazol-2-yl)acetonitrile (1 g, 6.36 mmol) and TEA (887μl, 6.36 mmol) were dissolved in THF (20 ml) and BOC anhydride (1.64 g,7.51 mmol) was added. The mixture was stirred at room temperature for 16h. The reaction mixture was concentrated in vacuo. The residue wasdissolved in chloroform and washed with 1 M HCl (aq) (50 ml), sat.NaHCO₃ (aq) (50 ml) and brine (50 ml). The organic phase was dried(Na₂SO₄), filtered and evaporated in vacuo. Purification by flashchromatography using an elution gradient 10-30% EtOAc/heptane affordedthe title compound (923 mg, 56%) as an orange solid followingtrituration with DCM/heptane.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=8.00-7.91 (m, 1H), 7.84-7.74 (m, 1H),7.48-7.36 (m, 2H), 4.37 (s, 2H), 1.77 (s, 9H)

HPLCMS (Method A): [m/z]: 158.35 [M+H-Boc]⁺

Tert-butyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,3-benzodiazole-1-carboxylate(297)

A suspension of tert-butyl2-(cyanomethyl)-1H-1,3-benzodiazole-1-carboxylate (296) (597 mg, 2.32mmol), TEA (258 mg, 2.55 mmol), Boc₂O (557 mg, 2.55 mmol) and Pd (10% wton carbon, 247 mg, 0.23 mmol) in EtOH (20 ml) was stirred under anatmosphere of hydrogen for 16 h. The reaction mixture was filteredthrough a plug of Celite and the residue rinsed with MeOH and 7 Nammonia in MeOH. The combined filtrates were evaporated in vacuo.Purification by flash chromatography using an elution gradient 0-60%EtOAc/heptane afforded the title compound (748 mg, 89%) as a whitesolid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.99-7.90 (m, 1H), 7.75-7.67 (m, 1H),7.39-7.31 (m, 2H), 5.50 (s, 1H), 3.76 (q, J=5.7 Hz, 2H), 3.36 (t, J=5.7Hz, 2H), 1.73 (s, 9H), 1.43 (s, 9H)

HPLCMS (Method A): [m/z]: 362.1 [M+H]⁺

Ethyl 3-(bromomethyl)-1-methyl-1H-pyrazole-5-carboxylate (298)

Ethyl 1,3-dimethyl-1H-pyrazole-5-carboxylate (433 mg, 2.57 mmol), NBS(0.623 g, 3.5 mmol) and AIBN (40 mg) in DCE (10 ml) was heated at 80° C.for 1.5 h. The reaction mixture was cooled to room temperature andevaporated in vacuo. Purification by flash chromatography using anelution gradient 0-10% Et₂O/heptane afforded the title compound (419 mg,66%) as a white waxy solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=6.90 (s, 1H), 4.48 (s, 2H), 4.36 (q,J=7.1 Hz, 3H), 4.18 (s, 3H), 1.40 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 246.75/248.75 [M+H]⁺

Tert-butyl2-(2-{[(tert-butoxy)carbonyl]({[5-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]methyl})amino}ethyl)-1H-1,3-benzodiazale-1-carboxylate(299)

Tert-butyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1H-1,3-benzodiazole-1-carboxylate(298) (263 mg, 0.73 mmol) in THF (5 ml) was cooled in an ice/water bath.NaBH₄ (60% in mineral oil, 60 mg, 1.5 mmol) was added and the mixturestirred for 5 min. Ethyl3-(bromomethyl)-1-methyl-1H-pyrazole-5-carboxylate (297) (90 mg, 0.36mmol) in THF (2 ml) was added, the mixture allowed to warm to roomtemperature and stirred for 10 min. The reaction mixture was quenched bydropwise addition of water, then further diluted with water andextracted with DCM (3×20 ml). The combined organic extracts were dried(Na₂SO₄), filtered and evaporated in vacuo. Purification by flashchromatography using an elution gradient 0-80% EtOAc/heptane affordedthe title compound (126 mg, 66%) as a colourless oil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=7.68-7.62 (m, 1H), 7.32-7.27 (m, 1H),7.18-7.13 (m, 2H), 6.43 (s, 1H), 5.26 (s, 2H), 4.19 (q, J=7.1 Hz, 2H),4.09-4.06 (m, 2H), 4.05 (s, 3H), 3.18 (dd, J=8.4, 6.8 Hz, 2H), 1.39 (s,18H), 1.23 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 528.2 [M+H]⁺

3-({[(Tert-butoxy)carbonyl](2-{1-[(tert-butoxy)carbonyl]-1H-1,3-benzodiazol-2-yl}ethyl)amino}methyl)-1-methyl-1H-pyrazole-5-carboxylicacid (300)

In a similar fashion to general procedure 5, tert-butyl2-(2-{[(tert-butoxy)carbonyl]({[5-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]methyl})amino}ethyl)-1H-1,3-benzodiazale-1-carboxylate(299) (126 mg, 0.24 mmol) and LiOH (17 mg, 0.72 mmol) in THF (5 ml) andwater (5 ml) afforded the title compound (152 mg) as a pale yellow oil.

HPLCMS (Method A): [m/z]: 500.15 [M+H]⁺

Tert-butyl2-(2-{[(tert-butoxy)carbonyl][(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1-methyl-1H-pyrazol-3-yl)methyl]amino}ethyl)-1H-1,3-benzodiazole-1-carboxylate(301)

In a similar fashion to general procedure 6, tert-butyl2-(2-{[(tert-butoxy)carbonyl]({[5-(ethoxycarbonyl)-1-methyl-1H-pyrazol-3-yl]methyl})amino}ethyl)-1H-1,3-benzodiazale-1-carboxylate(300) (130 mg, 0.26 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (57 mg, 0.29 mmol), DIPEA (150 μl, 0.86 mmol) andHATU (119 mg, 0.31 mmol) in DCM (10 ml) afforded the crude titlecompound (317 mg, 30% purity) as a white solid which was used in thenext step without purification.

HPLCMS (Method A): [m/z]: 608.2 [M+H]⁺

3-({[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}methyl)-N-[(3-fluoropyridin-2-yl)methyl]-1-methyl-1H-pyrazole-5-carboxamide(Example Compound No. 220)

In a similar fashion to general procedure 2, tert-butyl2-(2-{[(tert-butoxy)carbonyl][(5-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1-methyl-1H-pyrazol-3-yl)methyl]amino}ethyl)-1H-1,3-benzodiazole-1-carboxylate(301) (30%, 317 mg, 0.16 mmol) and 12 M HCl (0.63 ml) in MeOH (5 ml) at60° C. for 15 min afforded the title compound (44 mg, 69%) as a whitesolid after purification by basic prep-HPLC

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.93 (m, 1H), 8.34 (dt, J=4.6, 1.4 Hz,1H), 7.72-7.63 (m, 1H), 7.56 (m, 1H), 7.52 (dd, J=7.0, 1.4 Hz, 1H),7.43-7.33 (m, 1H), 7.21-7.11 (m, 2H), 6.71 (s, 1H), 5.41 (s, 2H),4.57-4.49 (m, 2H), 4.00 (s, 3H), 3.05-2.96 (m, 4H)

HPLCMS (Method C): [m/z]: 408.1 [M+H]⁺

General Scheme 19 Above Methyl2-bromo-1-methyl-1H-imidazole-4-carboxylate (302)

To a stirring solution of methyl 1-methyl-1H-imidazole-4-carboxylate (5g, 46.38 mmol) in THF (100 ml) was added NBS (8.25 g, 46.38 mmol). Thereaction mixture was allowed to stir at room temperature for 72 h. Themixture was concentrated and the crude residue was dissolved in EtOAc(80 ml), washed with sat. Na₂S₂O₃ (100 ml) and a pH 12 solution of NaOH(50 ml). The NaOH solution was extracted using 1:4 IPA:CHCl3 (5×10 ml)and the organic layers were combined, dried over MgSO₄, filtered andconcentrated to give the crude product. Purification by columnchromatography with a gradient of 0-100% EtOAc/heptane gave the purifiedproduct which was dissolved in a pH12 solution of NaOH (50 ml) andextracted using DCM. The organic layers were combined, dried over MgSO₄,filtered and concentrated to give the title compound (5.58 g, 71%) as awhite solid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.08 (s, 1H), 3.74 (s, 3H), 3.63 (s,3H)

HPLCMS (Method A): [m/z]: 218.8, 220.75 [M+H]⁺

Methyl 2-formyl-1-methyl-1H-imidazole-4-carboxylate (303)

To an N₂ purged stirring solution of methyl2-bromo-1-methyl-1H-imidazole-4-carboxylate (302) (200 mg, 0.91 mmol) inTHF (1 ml) at −40° C. was added dropwise 2 M iPrMgCl in THF (3.31 ml,6.62 mmol). After 20 min, the reaction was cooled to −78° C. and DMF(1.08 ml, 13.96 mmol) added dropwise. The reaction was allowed to warmto room temperature, after 40 min, the reaction was quenched with sat.NaHCO₃ (10 ml) which gave a thick white emulsion. The product wasextracted with EtOAc (5×10 ml). The combined organic layers were driedover MgSO₄, filtered and concentrated to give the crude product.Purification by silica flash column chromatography with a gradient of0-70% EtOAc/heptane gave the title compound (128 mg, 66%) as a whitesolid.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=9.74 (d, J=0.7 Hz, 1H), 8.26 (s, 1H),3.96 (s, 3H), 3.80 (s, 3H)

HPLCMS (Method A): [m/z]: 168.9 [M+H]⁺

Methyl 2-(1-hydroxy-2-nitroethyl)-1-methyl-1H-imidazole-4-carboxylate(304)

To a stirring solution of methyl2-formyl-1-methyl-1H-imidazole-4-carboxylate (303) (523 mg, 1.47 mmol),MeOH (12 ml) and nitromethane (78.9 μl, 1.47 mmol) followed by dropwiseaddition of 1 M NaOH solution (12 ml), the reaction was allowed to warmto room temperature over the duration of the experiment.

After 1 h, the solution was acidified using 2 M HCl to pH 4 andconcentrated to remove methanol. The aqueous layer was extracted with1:4 IPA/CHCl₃ (4×10 ml) and the combined organic layers were dried overMgSO₄, filtered and concentrated to give the crude product, which waspurified by silica flash column chromatography with a gradient of 0-80%EtOAc/heptane to give the final product (165 mg, 36%) as an off-whiteoil.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=7.94 (s, 1H), 6.35 (d, J=7.7 Hz, 1H),5.40 (m, 1H), 5.13 (dd, J=13.3, 4.0 Hz, 1H), 4.90 (dd, J=13.3, 9.4 Hz,1H), 3.75 (s, 3H), 3.73 (s, 3H)

HPLCMS (Method A): [m/z]: 229.9 [M+H]⁺

Methyl 1-methyl-2-[(E)-2-nitroethenyl]-1H-imidazole-4-carboxylate (305)

A stirring solution of methyl2-(1-hydroxy-2-nitroethyl)-1-methyl-1H-imidazole-4-carboxylate (304)(197 mg, 0.64 mmol) and acetic anhydride (3.5 ml) was heated to 45° C.After 4 h, the reaction was concentrated to give a yellow residue whichwas partitioned between sat. NaHCO₃ (20 ml) and EtOAc (20 ml). Theorganic layer was separated and the aqueous extracted using EtOAc (4×5ml). The combined organic layers were dried over MgSO₄, filtered andconcentrated to give the crude product, purified by silica flash columnchromatography with a gradient of 20-100% EtOAc/heptane to give therequired product (97 mg, 60%) as a yellow solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.19 (s, 1H), 8.02-7.93 (m, 2H), 3.89(s, 3H), 3.78 (s, 3H)

HPLCMS (Method A): [m/z]: 211.9 [M+H]⁺

Methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1-methyl-1H-imidazole-4-carboxylate(306)

To an N₂ purged stirring solution of methyl1-methyl-2-[(E)-2-nitroethenyl]-1H-imidazole-4-carboxylate (305) (110mg, 0.44 mmol), di-tert-butyl dicarbonate (386.5 mg, 1.77 mmol) and EtOH(5 ml) was added Pd/C (10%) (47.1 mg, 0.04 mmol). The reaction waspurged (×3) with N₂ followed by H₂. After 48 h, the reaction wasfiltered under vacuum through glass fibre paper using methanol (20 ml)to wash the filter cake and the filtrate was concentrated to give thecrude product. The crude was purified by flash column chromatography(eluting with a gradient of 0-8% MeOH/DCM) to give the purified product(75 mg, 26%) as a yellow solid.

HPLCMS (Method A): [m/z]: 284 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}ethyl)-1-methyl-1H-imidazole-4-carboxylicacid (307)

In a similar fashion to general procedure 5, methyl2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1-methyl-1H-imidazole-4-carboxylate(306) (0.5 g, 0.79 mmol) and LiOH (0.19 g, 7.94 mmol) in THF (20 ml) andwater (10 ml) gave the crude product as a yellow solid (0.703 g, quant.)

HPLCMS (Method A): [m/z]: 270.05 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1-methyl-1H-imidazol-2-yl)ethyl]carbamate(308)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-1-methyl-1H-imidazole-4-carboxylicacid (307) (0.703 g, 0.79 mmol), HATU (0.604 g, 1.59 mmol),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.316 g, 1.58mmol) and DIPEA (0.968 ml, 5.56 mmol) in THF (20 ml) and DMF (5 ml) atroom temperature for 3 h gave the title compound (0.092 g, 30%) as ayellow solid after purification by flash column chromatography (elutingwith a gradient of 0-9% MeOH/DCM)

HPLCMS (Method A): [m/z]: 378.15 [M+H]⁺

2-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1-methyl-1H-imidazole-4-carboxamide(309)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1-methyl-1H-imidazol-2-yl)ethyl]carbamate(308) (94 mg, 0.25 mmol) and 12M HCl (0.415 ml, 4.98 mmol) in MeOH (4ml) at 40° C. for 2 h gave the product (9 mg, 13%) as a brown solidafter flushing through a the column with 7 M NH₃/MeOH (×3).

HPLCMS (Method D): [m/z]: 278.05 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1-methyl-1H-imidazole-4-carboxamide (Example CompoundNo. 210)

In a similar fashion to general procedure 3,2-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1-methyl-1H-imidazole-4-carboxamide(309) (9 mg, 0.032 mmol), anhydrous MgSO₄ (150 mg),1H-benzimidazole-2-carbaldehyde (6.2 mg, 0.042 mmol) and DIPEA (11.3 μl,0.065 mmol) in MeOH (2 ml) for 72 h, followed by the addition of NaBH₄(1.8 mg, 0.049 mmol) gave the title compound (4.1 mg, 30%) as a brownsolid after purification by flash column chromatography with a gradientof 0-50% MeOH/DCM.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.18 (d, J=4.7 Hz, 1H), 7.49-7.44 (m,1H), 7.44 (s, 1H), 7.42-7.37 (m, 2H), 7.28-7.22 (m, 1H), 7.11-7.06 (m,2H), 4.63 (s, 2H), 3.97 (s, 2H), 3.53 (s, 3H), 2.97 (t, J=6.6 Hz, 2H),2.81 (t, J=6.6 Hz, 2H)

HPLCMS (Method A): [m/z]: 408.1 [M+H]⁺

General Scheme 20 Above Ethyl1-(cyanomethyl)-5-methyl-1H-imidazole-4-carboxylate (310)

To a N₂ purged, stirring solution of NaH (60% in oil) (0.856 g, 21.41mmol) in DMF (10 ml) at 0° C. was added a solution of ethyl4-methyl-1H-imidazole-5-carboxylate (3 g, 19.46 mmol) in DMF (25 ml)dropwise. After 10 min, bromoacetonitrile (1.63 ml, 23.35 mmol) wasadded dropwise to the solution giving a red mixture. The reaction wasallowed to warm to room temperature. After 16 h, the reaction wasconcentrated and the residue diluted with sat. NaHCO₃ (40 ml). Thesolution was extracted with EtOAc (6×20 ml) and the combined organiclayers were washed with brine (4×15 ml), dried over MgSO₄, filtered andconcentrated to give the crude product. Purification by flash columnchromatography with a gradient of 0-6% MeOH/DCM gave the title compound(1.3 g, 35%) as an orange solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=7.76 (s, 1H), 5.38 (s, 2H), 4.22 (q,J=7.1 Hz, 2H), 2.52 (s, 3H), 1.27 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 194 [M+H]⁺

Ethyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-4-methyl-1H-imidazole-4-carboxylate(311)

To a N₂ purged stirring solution of ethyl1-(cyanomethyl)-5-methyl-1H-imidazole-4-carboxylate (310) (0.72 g, 3.73mmol), EtOH (20 ml), TEA (0.675 ml, 4.85 mmol) and di-tert-butyldicarbonate (1.06 g, 4.85 mmol) at room temperature was added Pd/C (10%)(0.397 g, 0.37 mmol). The reaction was purged with N₂ (×3) followed byH₂. After 16 h, the reaction was filtered through glass fibre paper andthe filter cake washed with 7 M NH₃/MeOH (40 ml). The filtrate wasconcentrated to give the crude product which was further purified byflash column chromatography using a gradient of 0-10% MeOH/DCM yieldingthe required product (1.07 g, 84%) as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=7.53 (s, 1H), 7.01-6.93 (m, 1H), 4.19(q, J=7.1 Hz, 2H), 3.97 (t, J=5.9 Hz, 2H), 3.19 (q, J=6.0 Hz, 2H), 2.43(s, 3H), 1.37-1.32 (m, 9H), 1.28-1.23 (m, 3H)

HPLCMS (Method A): [m/z]: 298.1 [M+H]⁺

Lithium1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1H-imidazole-4-carboxylate(312)

To a stirring solution of ethyl1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1H-imidazole-4-carboxylate(311) (1.07 g, 3.12 mmol), THF (35 ml) and water (10 ml) was added LiOH(0.224 g, 9.36 mmol), the reaction was heated to 50° C. After 24 h, thereaction was concentrated to give the lithium salt of the product (0.670g) as a yellow solid.

HPLCMS (Method A): [m/z]: 270.05 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1H-imidazol-1-yl)ethyl]carbamate(313)

In a similar fashion to general procedure 6, lithium1-(2-{[(tert-butoxy)carbonyl]amino}ethyl)-5-methyl-1H-imidazole-4-carboxylate(312) (0.670 g, 2.488 mmol), THF (30 ml), DMF (10 ml) and DIPEA (1.733ml, 9.952 mmol) at room temperature was added HATU (1.419 g, 3.732 mmol)and (3-fluoropyridin-2-yl)methanamine dihydrochloride (0.743 g, 3.732mmol). After 2 h, the reaction mixture was concentrated and the residuedissolved in sat. NaHCO₃ (100 ml) which was extracted with EtOAc (6×20ml). The combined organic layers were washed with brine (3×20 ml), driedover MgSO₄, filtered and concentrated to give the crude product whichwas further purified by silica column chromatography with a gradient of0-10% MeOH in DCM to give an orange oil, further purified using a kp-NHsilica column chromatography with a gradient of 0-100% EtOAc in heptaneto give the final product (0.320 g, 31%) as a yellow oil.

1H-NMR (DMSO-d6, 500 MHz,) d[ppm]=8.39 (d, J=4.6 Hz, 1H), 8.22 (t, J=5.4Hz, 1H), 7.70 (t, J=9.3 Hz, 1H), 7.54 (s, 1H), 7.45-7.37 (m, 1H), 6.98(t, J=5.6 Hz, 1H), 4.60 (d, J=4.4 Hz, 2H), 3.96 (t, J=6.0 Hz, 2H), 3.19(q, J=5.9 Hz, 2H), 2.44 (s, 3H), 1.39-1.20 (m, 9H)

HPLCMS (Method A): [m/z]: 378.05 [M+H]⁺

1-(2-Aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1H-imidazole-4-carboxamidedihydrochloride (314)

In a similar fashion to general procedure 2, To a stirred solution oftert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-5-methyl-1H-imidazol-1-yl)ethyl]carbamate(313) (0.320 g, 0.776 mmol) in MeOH (10 ml) at room temperature wasadded conc. HCl (1.293 ml, 15.52 mmol), the reaction was heated to 50°C. After 2 h, the reaction was concentrated to give the required product(0.294 g, quant) as a yellow solid.

1H-NMR (Methanol-d4, 500 MHz): d[ppm]=9.03 (s, 1H), 8.54 (s, 1H), 8.06(s, 1H), 7.75 (s, 1H), 4.89 (s, 2H), 4.58 (t, J=6.5 Hz, 2H), 3.48 (t,J=6.4 Hz, 2H), 2.67 (s, 3H)

HPLCMS (Method A): [m/z]: 277.95 [M+H]⁺

1-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1H-imidazole-4-carboxamide(Example Compound No. 219)

In a similar fashion to general procedure 8,1-(2-aminoethyl)-N-[(3-fluoropyridin-2-yl)methyl]-5-methyl-1H-imidazole-4-carboxamidedihydrochloride (314) (0.294 g, 0.77 mmol), DBU (0.347 ml, 2.33 mmol)and N-(2-nitrophenyl)prop-2-enamide (D) (0.332 g, 1.73 mmol) in MeCN (20ml) followed by silica column chromatography (0-3% MeOH in DCM) followedby reaction with AcOH (2 ml) and iron powder (0.041 g) gave the titlecompound (0.030 g, 30%) as an off-white solid after purification bybasic prep-HPLC followed by flash column chromatography (kp-NH, elutingwith a gradient 0-5% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.09 (br s, 1H), 8.39 (d, J=4.7 Hz,1H), 8.22 (t, J=5.5 Hz, 1H), 7.75-7.66 (m, 1H), 7.61 (s, 1H), 7.53-7.35(m, 3H), 7.13-7.06 (m, 2H), 4.60 (d, J=4.3 Hz, 2H), 3.97 (t, J=6.3 Hz,2H), 3.00-2.93 (m, 2H), 2.94-2.88 (m, 2H), 2.84 (t, J=6.3 Hz, 2H), 2.47(s, 3H)

HPLCMS (Method G): [m/z]: 422.1 [M+H]⁺

General Scheme 21 Above Ethyl2-{1-[(tert-butoxy)carbonyl]-3-chloroazetidin-3-yl}-5-chloro-1,3-thiazole-4-carboxylate(321)

Ethyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-thiazole-4-carboxylate(161) (1.15 g, 3.68 mmol) and hexachloroethane (0.83 g, 3 mmol) weredissolved in THF (40 ml) and cooled to −78° C. 2 M NaHMDS (1.75 ml) wasadded dropwise and the reaction mixture was left stirring at −78° C. for30 min. Further 2M NaHMDS (0.6 ml) were added and the reaction mixtureand left stirred at −78° C. for further 30 min. The reaction wasquenched with sat. NH₄Cl (aq), warmed to room temperature, diluted withwater and extracted with DCM (3×80 ml). The combined organic extractswere dried (Na₂SO₄), filtered and evaporated in vacuo. Two majorcomponents were identified in the crude mixture. Purification by flashcolumn chromatography (eluting with a gradient of 2-15% EtOAc/heptane)gave the title compound (456 mg, 32%) as a pale yellow oil.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=4.72 (d, J=9.2 Hz, 2H), 4.37 (q, J=7.1Hz, 2H), 4.32 (m, 2H), 1.40 (s, 9H), 1.35 (t, J=7.1 Hz, 3H)

HPLCMS (Method A): [m/z]: 402.9 [M+Na]⁺

2-{1-[(Tert-butoxy)carbonyl]-3-chloroazetidin-3-yl}-5-chloro-1,3-thiazole-4-carboxylicacid (322)

In a similar fashion to general procedure 5, ethyl2-{1-[(tert-butoxy)carbonyl]-3-chloroazetidin-3-yl}-5-chloro-1,3-thiazole-4-carboxylate(321) (450 mg, 1.18 mmol) and LiOH (0.08 g, 4 mmol) in THF (5 ml) andwater (5 ml) gave the crude title compound (461 mg) as a colourless oilwhich crystallised on standing.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=4.76 (dd, J=9.6, 1.0 Hz, 2H), 4.45 (dd,J=9.6, 1.0 Hz, 2H), 1.50 (s, 9H)

HPLCMS (Method A): [m/z]: 378.85 [M+Na]⁺

Tert-butyl3-chloro-3-(5-chloro-4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate(323)

In a similar fashion to general procedure 6,2-{1-[(tert-butoxy)carbonyl]-3-chloroazetidin-3-yl}-5-chloro-1,3-thiazole-4-carboxylicacid (322) (460 mg, 1.3 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (311 mg, 1.56 mmol), DIPEA (0.75 ml, 4 mmol) andHATU (0.59 g, 2 mmol) in DCM (10 ml) afforded the title compound (479mg, 80%) after purification by flash column chromatography (eluting witha gradient of 10-50% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.34 (dt, J=4.7, 1.1 Hz, 1H), 8.26-8.20(m, 1H), 7.38-7.31 (m, 1H), 7.23-7.16 (m, 1H), 4.75 (m, 2H), 4.70 (m,2H), 4.35 (m, 2H), 1.40 (s, 9H)

HPLCMS (Method A): [m/z]: 460.95 [M+H]⁺

5-Chloro-2-(3-chloroazetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(324)

In a similar fashion to general procedure 2, tert-butyl3-chloro-3-(5-chloro-4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)azetidine-1-carboxylate(323) (479 mg, 1.04 mmol) and 12 M HCl (2 ml) in MeOH (20 ml) gave thetitle compound (375 mg, quant.) as a white solid following purificationusing an SCX-2 cartridge, rinsing with DCM and MeOH, then eluting with 7N ammonia in MeOH.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=9.05-8.96 (m, 1H), 8.40 (dt, J=4.6,1.4 Hz, 1H), 7.78-7.66 (m, 1H), 7.48-7.37 (m, 1H), 4.66 (dd, J=5.8, 1.6Hz, 2H), 4.41 (d, J=10.5 Hz, 2H), 4.07 (d, J=10.5 Hz, 2H)

HPLCMS (Method A): [m/z]: 360.8 [M+H]⁺

2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 209) and2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-3-hydroxyazetidin-3-yl}-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 211)

In a similar fashion to general procedure 8,5-chloro-2-(3-chloroazetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(324) (375 mg, 1.04 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (219 mg,1.14 mmol) and DBU (0.17 ml, 1.14 mmol) in MeCN (20 ml) gave a crudemixture which was further reacted with iron powder (0.2 g) in AcOH (5ml). Purification by basic prep-HPLC followed by flash columnchromatography (eluting with a gradient of 0-20% MeOH/DCM) gave thetitle compound (Example Compound No. 209) (60 mg, 14%) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.14 (s, 1H), 8.77 (t, J=5.6 Hz, 1H),8.38 (dt, J=4.6, 1.3 Hz, 1H), 7.75-7.67 (m, 1H), 7.56-7.37 (m, 3H), 7.12(dd, J=5.9, 2.6 Hz, 2H), 4.66-4.60 (m, 2H), 3.89 (ddd, J=13.1, 7.4, 5.6Hz, 1H), 3.61 (t, J=7.2 Hz, 2H), 2.94-2.88 (m, 2H), 2.87-2.81 (m, 2H).One CH₂ signal is obscured by the water peak.

HPLCMS (Method C): [m/z]: 471.1 [M+H]⁺

A byproduct was also isolated by basic prep-HPLC to give2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]-3-hydroxyazetidin-3-yl}-5-chloro-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 211) (2 mg) as a white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.16 (s, 1H), 8.86 (t, J=5.5 Hz, 1H),8.35 (dt, J=4.6, 1.4 Hz, 1H), 7.74-7.67 (m, 1H), 7.54-7.48 (m, 1H),7.44-7.34 (m, 2H), 7.15-7.07 (m, 2H), 4.65 (d, J=5.5 Hz, 2H), 3.70 (d,J=8.3 Hz, 2H), 3.43 (d, J=8.3 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.87 (t,J=7.2 Hz, 2H)

HPLCMS (Method C): [m/z]: 487.1 [M+H]⁺

General Scheme 22 Above Tert-butyl(1R,5S,6S)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (325)

In a similar fashion to general procedure 12,(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexane-6-carboxylicacid (1 g, 4.4 mmol), TEA (1.04 ml, 0.01 mol), isobutyl chloroformate(0.86 ml, 0.01 mol) and NH₃ 28% aqueous (1.33 ml, 0.07 mol) in THF (15ml) gave the crude title product (1.20 g) as a pale yellow solid. Thematerial was used directly in the next step.

HPLCMS (Method A): [m/z]: 249.05 [M+Na]⁺

Tert-butyl(1R,5S,6S)-6-carbamothioyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (326)

In a similar fashion to general procedure 11, tert-butyl(1R,5S,6S)-6-carbamoyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (325)(1.2 g, 5.3 mmol) and Lawesson reagent (1.18 g, 2.9 mmol) in DCM (40 ml)gave the title compound (939 mg, 73%) as a white foam after purificationby flash column chromatography using a gradient elution of 0-10%EtOAc/heptane.

HPLCMS (Method A): [m/z]: 242.95 [M+H]⁺

Tert-butyl(1R,5S,6R)-6-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(327)

In a similar fashion to general procedure 1, tert-butyl(1R,5S,6S)-6-carbamothioyl-3-azabicyclo[3.1.0]hexane-3-carboxylate (326)(939 mg, 3.87 mmol), ethyl 3-bromo-2-oxopropanoate (0.53 ml, 4 mmol) andCaCO₃ (0.21 g, 2 mmol) in EtOH (20 ml) afforded the title compound (546mg, 42%) as a colourless residue after purification by flash columnchromatography using a isocratic elution of 30% EtOAc/heptane followedby a second flash column chromatography using a gradient elution of0-40% EtOAc/heptane.

HPLCMS (Method A): [m/z]: 339.1 [M+H]⁺

2-[(1R,5S,6R)-3-[(Tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]-1,3-thiazole-4-carboxylicacid (328)

In a similar fashion to general procedure 5, tert-butyl(1R,5S,6R)-6-[4-(ethoxycarbonyl)-1,3-thiazol-2-yl]-3-azabicyclo[3.1.0]hexane-3-carboxylate(327) (546 mg, 1.61 mmol) and LiOH (0.12 g, 5 mmol) in THF (20 ml) andwater (10 ml) afforded the crude title compound (500 mg, 1.61 mmol) as apale yellow oil which was used in the next step without purification.

HPLCMS (Method A): [m/z]: 311.1 [M+H]⁺

Tert-butyl(1R,5S,6S)-6-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(329)

In a similar fashion to general procedure 6,2-[(1R,5S,6R)-3-[(tert-butoxy)carbonyl]-3-azabicyclo[3.1.0]hexan-6-yl]-1,3-thiazole-4-carboxylicacid (328) (500 mg, 1.61 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (352.7 mg, 1.77 mmol), DIPEA (0.93 ml, 5.31 mmol)and HATU (0.74 g, 1.93 mmol) in DCM (30 ml) afforded the title compound(650 mg, 96%) as a colourless foam after purification by flash columnchromatography eluting with a gradient of 20-100% EtOAc/heptane.

HPLCMS (Method A): [m/z]: 419.1 [M+H]⁺

2-[(1R,5S,6S)-3-Azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(330)

In a similar fashion to general procedure 4, tert-butyl(1R,5S,6S)-6-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate(329) (624 mg, 1.49 mmol) and 12 M HCl (2 ml) in MeOH (20 ml) affordedthe title compound (475 mg, 83%) after purification using an SCX-2cartridge, rinsing with DCM and MeOH, then elution with 7 N ammonia inMeOH.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.65 (t, J=5.6 Hz, 1H), 8.39 (dt,J=4.6, 1.3 Hz, 1H), 8.03 (s, 1H), 7.75-7.69 (m, 1H), 7.45-7.39 (m, 1H),4.67-4.63 (m, 2H), 3.05 (m, 3H), 2.78 (d, J=11.4 Hz, 2H), 2.38 (t, J=3.3Hz, 1H), 2.03-2.00 (m, 2H)

HPLCMS (Method A): [m/z]: 319.05 [M+H]⁺

2-[(1R,5S,6S)-3-(1H-1,3-Benzodiazol-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(331)

In a similar fashion to general procedure 3,2-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(330) (200 mg, 0.63 mmol), 1H-1,3-benzodiazole-2-carbaldehyde (110.17mg, 0.75 mmol), DIPEA (0.33 ml, 2 mmol) and MgSO₄ (300 mg) in MeOH (10ml) at room temperature for 18 h, followed by addition of NaBH₄ (48 mg,1.3 mmol) gave the title compound (62 mg, 22%) as a pale yellow solidafter trituration of the residue in 1:1 DMSO/MeCN followed by rinsingwith MeOH.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.63 (t, J=5.7 Hz, 1H),8.40 (d, J=4.6 Hz, 1H), 8.04 (s, 1H), 7.76-7.67 (m, 1H), 7.55 (d, J=7.8Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 7.44-7.39 (m, 1H), 7.20-7.09 (m, 2H),4.66 (d, J=4.9 Hz, 2H), 3.91 (s, 2H), 3.15 (d, J=9.1 Hz, 2H), 2.96 (t,J=2.8 Hz, 1H), 2.66-2.60 (m, 2H), 2.14-2.10 (m, 2H)

HPLCMS (Method C): [m/z]: 449.1 [M+H]⁺

2-[(1R,5S,6S)-3-(1H-1,3-Benzodiazol-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 213)

2-[(1R,5S,6S)-3-(1H-1,3-benzodiazol-2-ylmethyl)-3-azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(331) (20 mg, 0.44 mmol) was suspended in MeOH (3 ml) and treated with12 M HCl (0.5 ml), causing dissolution. The mixture was stirred for 1 h,evaporated under vacuum to give the title compound (25 mg, quant.) as ayellow solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.58-8.55 (m, 1H), 8.19-8.13 (m, 1H),8.05 (s, 1H), 7.86-7.78 (m, 3H), 7.66-7.61 (m, 2H), 4.90 (s, 2H), 4.52(s, 2H), 3.60-3.52 (m, 2H), 3.22-3.13 (m, 2H), 3.11 (t, J=3.1 Hz, 1H),2.43 (s, 2H)

HPLCMS (Method C): [m/z]: 449.1 [M+H]⁺

2-[(1R,5S,6S)-3-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]-3-azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 218)

In a similar fashion to general procedure 8,2-[(1R,5S,6S)-3-azabicyclo[3.1.0]hexan-6-yl]-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(330) (264 mg, 0.83 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (175 mg,0.91 mmol) and DBU (0.14 ml, 0.91 mmol) in MeCN (15 ml) gave a crudeintermediate which was further reacted with iron powder (180 mg, 3.2mmol) in AcOH (5 ml) to give the title compound (4 mg, 1%) as acolourless residue after purification by sequential flash chromatography(eluting with a gradient of 0-40% MeOH/DCM), basic prep-HPLC and flashcolumn chromatography (eluting with a gradient of 0-5% MeOH/DCM).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.38 (d, J=4.7 Hz, 1H), 7.94 (s, 1H),7.61 (ddd, J=9.7, 8.4, 1.2 Hz, 1H), 7.53 (m, 2H), 7.43-7.38 (m, 1H),7.22 (m, 2H), 4.77 (d, J=1.5 Hz, 2H), 3.30 (m, 2H), 3.09 (m, 2H), 3.01(m, 2H), 2.66 (m, 1H), 2.58 (m, 2H), 2.15 (s, 2H)

HPLCMS (Method C): [m/z]: 463.1 [M+H]⁺

2-(2-{[2-(1H-1,3-Benzodiazol-2-yl)ethyl](methyl)amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 223)

2-(2-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}ethyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 127) (59 mg, 0.14 mmol), TEA (60 μl, 0.43 mmol) inDMF (1 ml) were stirred at room temperature for 1 h. MeI (8.9 μl, 0.14mmol) was added and stirred at room temperature for 24 h. The reactionmixture was re-treated with MeI (62.9 μl, 0.79 mmol) and TEA (80 μl,0.58 mmol) and left stirring at room temperature for 2 d. The mixturewas vigorously reduced in vacuo to give a yellow oil (200 mg) which waspurification by basic prep-HPLC, followed by kp-NH column chromatography(eluting with a gradient of 0-10% MeOH/DCM) and flash columnchromatography (eluting with a gradient of 0-20% MeOH/DCM) to give thetitle compound (13 mg, 21%) as an off-white solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.34-8.29 (m, 1H), 8.15 (s, 1H),7.61-7.54 (m, 1H), 7.44 (br s, 2H), 7.38-7.33 (m, 1H), 7.19-7.13 (m,2H), 4.69 (d, J=1.6 Hz, 2H), 3.09-3.04 (m, 2H), 3.04-2.99 (m, 2H),2.98-2.91 (m, 4H), 2.39 (s, 3H)

HPLCMS (Method G): [m/z]: 423.1 [M+H]⁺

General Scheme 25 Above Tert-butyl3-[(3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl]azetidine-1-carboxylate(339)

A stirring solution of methyl serinate hydrochloride (1:1) (2.3 g, 14.78mmol) and TEA (2.27 ml, 16.26 mmol) in DCM (150 ml) was cooled to 0° C.1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (2.97 g, 14.78mmol) was added followed by addition of DCC (3.36 g, 16.26 mmol) portionwise, the reaction was then allowed to warm to room temperature. After24 h the mixture was concentrated and dissolved in EtOAc (250 ml). Thereaction mixture was left stirring at 50° C. for 45 min. The precipitatewas then filtered off and the filtrate was concentrated to give thecrude product as a white solid. Purification by flash columnchromatography using a gradient elution of 100% TBME followed byDCM/MeOH afforded the title compound (4.5 g, 91%) as a yellow solid.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=6.75 (d, 1H), 4.66 (dt, 1H), 4.14-4.02(m, 4H), 3.99 (dd, 1H), 3.88 (d, 1H), 3.77 (s, 3H), 3.29 (ddd, 1H), 1.42(s, 9H)

HPLCMS (Method A): [m/z]: 246.95 [M-^(t)Bu]⁺

Methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-4,5-dihydro-1,3-oxazole-4-carboxylate(340)

In a similar fashion to general procedure 14, tert-butyl3-[(3-hydroxy-1-methoxy-1-oxopropan-2-yl)carbamoyl]azetidine-1-carboxylate(339) (4.5 g, 13.4 mmol) and DAST (2.3 ml, 17.42 mmol) in DCM (120 ml)afforded the title compound (3.3 g, 78%) as a pale yellow oil. Compoundwas used into the next step without further purification.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=4.78 (m, 1H), 4.60-4.53 (m, 1H), 4.47(m, 1H), 4.12 (m, 4H), 3.80 (s, 3H), 3.48-3.36 (m, 1H), 1.43 (s, 9H)

Methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylate(341)

In a similar fashion to general procedure 15, methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-4,5-dihydro-1,3-oxazole-4-carboxylate(340) (3.3 g, 10.45 mmol), DBU (2.21 ml, 14.77 mmol) andbromo(trichloro)methane (2.57 ml, 26.12 mmol) in DCM (25 ml) affordedthe title compound (2.3 g, 70%) as an yellow oil after purification byflash column chromatography using a gradient of 0-10% MeOH in DCM.

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.21 (s, 1H), 4.30-4.24 (m, 4H),3.96-3.89 (m, 4H), 1.44 (s, 9H)

HPLCMS (Method A): [m/z]: 305.00 [M+Na]⁺

2-{1-[(Tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid(342)

In a similar fashion to general procedure 5, methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylate(341) (2.3 g, 7.33 mmol) and LiOH (0.26 g, 0.01 mol) in THF (35 ml) andwater (8.5 ml) at room temperature for 4 h afforded the title compound(2.0 g, 86%) as a pale yellow oil. The crude material was used in thenext step without further purification.

HPLCMS (Method A): [m/z]: 290.95 [M+Na]⁺

2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid(343)

In a similar fashion to general procedure 6, tert-butyl3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}azetidine-1-carboxylate(342) (1 g, 3.17 mmol), pyridin-2-ylmethanamine (0.343 g, 3.17 mmol),TEA (0.42 ml, 3.17 mmol) and HATU (1.81 g, 4.75 mmol) in DMF (10 ml) atroom temperature for 48 h afforded the title compound (1.07 g, 32%) as abrown oil after purification by flash column chromatography (elutingwith a gradient of 40-80% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.55-8.51 (m, 1H), 8.11 (s, 1H), 7.84(s, 1H), 7.61 (td, J=7.7, 1.8 Hz, 1H), 7.25 (d, J=7.8 Hz, 1H), 7.15 (dd,J=7.4, 4.9 Hz, 1H), 4.67 (d, J=5.5 Hz, 2H), 4.22 (t, J=8.8 Hz, 2H), 4.16(dd, J=8.6, 6.2 Hz, 2H), 3.86-3.78 (m, 1H), 1.39 (s, 9H)

HPLCMS (Method A): [m/z]: 359.10 [M+H]⁺

Tert-butyl3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)azetidine-1-carboxylate(344)

In a similar fashion to general procedure 6,2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid(342) (1.0 g, 3.48 mmol), (3-fluoropyridin-2-yl)methanaminedihydrochloride (A2) (0.83 g, 4.17 mmol), DIPEA (2.42 ml, 13.91 mmol)and HATU (1.59 g, 4.17 mmol) in THF (50 ml) and DMF (10 ml) afforded thetitle compound (1.56 g, 90%) as a yellow oil after purification by flashcolumn chromatography (eluting with a gradient of 20-100%EtOAc/heptane).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.68-8.54 (m, 2H), 8.38 (d, J=4.6 Hz,1H), 7.75-7.63 (m, 1H), 7.40 (m, 1H), 4.66-4.57 (m, 2H), 4.31-4.15 (m,2H), 4.11-3.95 (m, 3H), 1.39 (s, 9H)

HPLCMS (Method A): [m/z]: 377.15 [M+H]⁺

Tert-butyl3-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}azetidine-1-carboxylate(345)

In a similar fashion to general procedure 6,2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylic acid(342) (0.8 g, 2.98 mmol), 1-(pyridazin-3-yl)methanamine (0.42 g, 3.28mmol, 85% purity), DIPEA (779 μl, 4.47 mmol) and HATU (1.36 g, 3.58mmol) in DCM (20 ml) afforded the title compound (0.90 g, 84%) as abrown residue after purification by flash column chromatography (elutingwith a gradient of 50-100% EtOAc/heptane followed by 0-20% MeOH/EtOAc).

HPLCMS (Method M): [m/z]: 360.00 [M+H]⁺

2-(Azetidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide (346)

In a similar fashion to general procedure 2, tert-butyl3-{4-[(pyridin-2-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}azetidine-1-carboxylate(343) (1.07 g, 2.99 mmol) and 12M HCl (2 ml) in MeOH (20 ml) at 50° C.for 30 min afforded the title compound (0.457 g, 59%) as a yellow solidafter purification using an SCX-2 cartridge (10 g), rinsing with DCM andMeOH and then eluting with 7N NH₃/MeOH. The basic eluent was thenconcentrated to give the title compound as the free base.

HPLCMS (Method A): [m/z]: 259.00 [M+H]⁺

2-(Azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (347)

In a similar fashion to general procedure 2, tert-butyl3-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-oxazol-2-yl)azetidine-1-carboxylate(344) (1.56 g, 3.12 mmol) and concentrated HCl (5.2 ml, 62.51 mmol) inMeOH (25 ml) at room temperature for 16 h afforded the title compound(1.31 g, quant.) as an off-white solid. The crude material was used inthe next step without purification.

HPLCMS (Method A): [m/z]: 277.05 [M+H]⁺

2-(Azetidin-3-yl)-N-(pyridazin-3-ylmethyl)-1,3-oxazole-4-carboxamide(348)

In a similar fashion to general procedure 2, tert-butyl3-{4-[(pyridazin-3-ylmethyl)carbamoyl]-1,3-oxazol-2-yl}azetidine-1-carboxylate(345) (900 mg, 2.5 mmol) and TFA (10 ml, 130.6 mmol) in DCM (10 ml) atroom temperature for 40 min afforded the title compound (447 mg, 69%) asa beige solid after purification using an SCX-2 cartridge (10 g),rinsing with DCM and MeOH and then eluting with 7N NH₃/MeOH. The basiceluent was then concentrated to give the title compound as the freebase.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=9.14 (dd, J=4.7, 1.7 Hz, 1H), 8.95 (t,J=6.0 Hz, 1H), 8.60 (s, 1H), 7.67 (dd, J=8.5, 4.7 Hz, 1H), 7.59 (dd,J=8.5, 1.8 Hz, 1H), 4.73 (d, J=6.2 Hz, 2H), 4.13-3.99 (m, 1H), 3.89-3.70(m, 4H)

HPLCMS (Method M): [m/z]: 260.00 [M+H]⁺

2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide(Example Compound No. 207)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide (346)(457 mg, 1.769 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (408 mg, 2.123mmol) and DBU (0.32 ml, 2.123 mmol) in MeCN (20 ml) gave the crudeintermediate which was purified by flash column chromatography (elutingwith a gradient of 0-5% MeOH/DCM). The intermediate was further reactedwith iron powder (134 mg) in AcOH (3 ml) to give the title compound (26mg, 8%) as a white solid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.50 (d, J=4.3 Hz, 1H), 8.33 (s, 1H),7.80 (m, 1H), 7.50 (s, 2H), 7.40 (d, J=7.9 Hz, 1H), 7.34-7.29 (m, 1H),7.22-7.16 (m, 2H), 4.67 (s, 2H), 3.88 (p, J=7.3 Hz, 1H), 3.75 (t, J=8.0Hz, 2H), 3.54 (t, J=7.5 Hz, 2H), 3.05-2.99 (m, 2H), 2.99-2.93 (m, 2H)HPLCMS (Method G): [m/z]: 403.2 [M+H]⁺

2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 208)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamidedihydrochloride (347) (0.657 g, 1.571 mmol), DBU (0.703 ml, 4.713 mmol)and N-(2-nitrophenyl)prop-2-enamide (D) (0.332 g, 1.728 mmol) in MeCN(30 ml) at room temperature for 4 h gave the crude intermediate whichwas purified by flash column chromatography (eluting with a gradient of0-3% MeOH/DCM) to give a yellow oil (0.778 g). This was further reactedwith iron powder (0.191 g) in AcOH (4 ml) at 80° C. for 2 h to give thetitle compound (0.072 g, 15%) as a white solid after purification byflash column chromatography (kp-NH, eluting with a gradient of 0-3%MeOH/DCM) followed by another flash column chromatography (eluting witha gradient of 0-20% MeOH/DCM).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.36 (d, J=4.7 Hz, 1H), 8.32 (s, 1H),7.62-7.56 (m, 1H), 7.50 (br s, 2H), 7.41-7.36 (m, 1H), 7.22-7.17 (m,2H), 4.75 (d, J=1.5 Hz, 2H), 3.88 (p, J=7.3 Hz, 1H), 3.75 (t, J=8.0 Hz,2H), 3.53 (t, J=7.5 Hz, 2H), 3.04-2.99 (m, 2H), 2.99-2.93 (m, 2H)

HPLCMS (Method C): [m/z]: 421.1 [M+H]⁺

2-{1-[2-(1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-(pyridazin-3-ylmethyl)-1,3-oxazole-4-carboxamide(Example Compound No. 244)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-(pyridazin-3-ylmethyl)-1,3-oxazole-4-carboxamide(348) (440 mg, 1.7 mmol), N-(2-nitrophenyl)prop-2-enamide (D) (326 mg,1.7 mmol) and DBU (279 μl, 1.87 mmol) in MeCN (20 ml) gave a crudeintermediate which was further reacted with iron powder (302 mg, 5.41mmol) in AcOH (5 ml) to afforded the title compound (82 mg, 15%) as awhite solid after purification by basic prep-HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=9.12 (dd, J=4.5, 2.1 Hz, 1H), 8.36 (s,1H), 7.76-7.69 (m, 2H), 7.51 (s, 2H), 7.24-7.19 (m, 2H), 4.88 (s, 2H),3.93-3.85 (m, 1H), 3.78-3.74 (m, 2H), 3.58-3.53 (m, 2H), 3.07-3.01 (m,2H), 3.01-2.95 (m, 2H)

HPLCMS (Method B): [m/z]: 404.2 [M+H]⁺

2-{1-[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 239)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide;bis(trifluoroacetic acid) (347) (700 mg, 1.39 mmol), DBU (1.04 ml, 6.94mmol) and N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (292 mg, 1.39mmol) in MeCN (30 ml) gave a crude intermediate which was furtherreacted with iron powder (173 mg, 3.1 mmol) in AcOH (5 ml) to afford thetitle compound (98 mg, 29%) as a pale pink solid after purification byflash column chromatography (eluting with a gradient of 0-8% MeOH/DCM).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.38 (dt, J=4.6, 1.1 Hz, 1H), 8.35 (s,1H), 7.62 (ddd, J=9.8, 8.4, 1.2 Hz, 1H), 7.41 (dt, J=8.6, 4.5 Hz, 1H),7.31 (d, J=8.1 Hz, 1H), 7.18 (td, J=8.1, 4.8 Hz, 1H), 6.95 (dd, J=10.8,8.0 Hz, 1H), 4.77 (d, J=1.5 Hz, 2H), 3.94-3.86 (m, 1H), 3.78 (t, J=7.9Hz, 2H), 3.57 (t, J=7.5 Hz, 2H), 3.08-3.03 (m, 2H), 3.02-2.97 (m, 2H)

HPLCMS (Method B): [m/z]: 439.2 [M+H]⁺

2-{1-[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide(Example Compound No. 258)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-(pyridin-2-ylmethyl)-1,3-oxazole-4-carboxamide (346)(0.88 g, 3.21 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G) (0.80g, 3.53 mmol) and DBU (580 μl, 3.86 mmol) in MeCN (30 ml) gave a crudeintermediate which was further reacted with iron powder (0.57 g, 10.24mmol) in AcOH (16 ml) to afford the title compound (0.59 g, 55%) as anoff-white solid after purification by flash column chromatography(eluting with a gradient of 0-15% MeOH/DCM) followed by basic prep-HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.51-8.48 (m, 1H), 8.33 (s, 1H), 7.80(td, J=7.7, 1.8 Hz, 1H), 7.40 (d, J=7.9 Hz, 1H), 7.34-7.27 (m, 2H), 7.16(td, J=8.1, 4.8 Hz, 1H), 6.92 (dd, J=10.8, 8.1 Hz, 1H), 4.67 (s, 2H),3.93-3.83 (m, 1H), 3.75 (t, J=7.9 Hz, 2H), 3.54 (t, J=7.5 Hz, 2H),3.05-3.00 (m, 2H), 2.99-2.95 (m, 2H)

HPLCMS (Method C): [m/z]: 421.3 [M+H]⁺

2-{1-[2-(4-Fluoro-1H-1,3-benzodiazol-2-yl)ethyl]azetidin-3-yl}-N-(pyridazin-3-ylmethyl)-1,3-oxazole-4-carboxamide(Example Compound No. 261)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-(pyridazin-3-ylmethyl)-1,3-oxazole-4-carboxamide(348) (417 mg, 1.61 mmol), N-(3-fluoro-2-nitrophenyl)prop-2-enamide (G)(372 mg, 1.77 mmol) and DBU (264 μl, 1.77 mmol) in MeCN (50 ml) gave acrude intermediate which was further reacted with iron powder (261 mg,4.67 mmol) in AcOH (10 ml) to afford the title compound (268 mg, 54%) asa white solid after purification by basic prep-HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=9.12 (dd, J=4.5, 2.1 Hz, 1H), 8.36 (s,1H), 7.76-7.70 (m, 2H), 7.31 (d, J=8.1 Hz, 1H), 7.18 (td, J=8.1, 4.8 Hz,1H), 6.97-6.91 (m, 1H), 4.88 (s, 2H), 3.89 (p, J=7.3 Hz, 1H), 3.79-3.74(m, 2H), 3.58-3.53 (m, 2H), 3.06-3.02 (m, 2H), 3.02-2.96 (m, 2H)

HPLCMS (Method B): [m/z]: 422.2 [M+H]⁺

N-[(3-Fluoropyridin-2-yl)methyl]-2-(1-{2-[7-(trifluoromethyl)-1H-1,3-benzodiazol-2-yl]ethyl}azetidin-3-yl)-1,3-oxazole-4-carboxamide(Example Compound No. 273)

In a similar fashion to general procedure 8,2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(347) (393 mg, 1.42 mmol),N-[2-nitro-6-(trifluoromethyl)phenyl]prop-2-enamide (K8) (474 mg, 1.42mmol, 78% purity) and DBU (0.23 ml, 1.56 mmol) in MeCN (18 ml) gave acrude intermediate which was further reacted with iron powder (280 mg,5.01 mmol) in AcOH (8 ml) to afford the title compound (197 mg, 32%) asa light brown foam after purification by flash column chromatography(eluting with a gradient of 0-20% MeOH/DCM).

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.64 (s, 1H), 8.55 (s, 1H), 8.52 (t,J=5.7 Hz, 1H), 8.39-8.35 (m, 1H), 7.76 (s, 1H), 7.71-7.65 (m, 1H),7.48-7.43 (m, 1H), 7.43-7.37 (m, 1H), 7.30-7.26 (m, 1H), 4.66-4.58 (m,2H), 3.81 (p, J=7.4 Hz, 1H), 3.63 (t, J=7.5 Hz, 2H), 3.35 (t, J=7.2 Hz,2H), 2.90 (s, 4H)

HPLCMS (Method D): [m/z]: 489.1 [M+H]⁺

General Scheme 26 Above2-(3-Chloropropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazole(349)

[2-(chloromethoxy)ethyl](trimethyl)silane (553 μl, 3.12 mmol) was addedto a solution of 2-(3-chloropropyl)-1H-1,3-benzodiazole hydrochloride(555 mg, 2.4 mmol) and DIPEA (962 μl, 5.52 mmol) in THF (25 ml). Thereaction mixture was stirred at room temperature for 18 h, then quenchedwith saturated NaHCO₃ (aq) and extracted with EtOAc (3×80 ml). Thecombined organic extracts were washed with brine (50 ml), dried (Na₂SO₄)and evaporated in vacuo. Purification by flash column chromatography(eluting with a gradient of 0-50% EtOAc/heptane) afforded the titlecompound (571 mg, 73%) as a pale yellow oil.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=7.85-7.75 (m, 1H), 7.53-7.44 (m, 1H),7.38-7.31 (m, 2H), 5.57 (s, 2H), 3.78 (t, J=6.1 Hz, 2H), 3.60 (dd,J=8.6, 7.7 Hz, 2H), 3.21 (t, J=7.3 Hz, 2H), 2.59-2.44 (m, 2H), 0.96 (dd,J=8.6, 7.7 Hz, 2H), 0.00 (s, 9H)

HPLCMS (Method M): [m/z]: 325.50 [M+H]⁺

Methyl 2-(azetidin-3-yl)-1,3-oxazole-4-carboxylate hydrochloride (350)

In a similar fashion to general procedure 4, methyl2-{1-[(tert-butoxy)carbonyl]azetidin-3-yl}-1,3-oxazole-4-carboxylate(341) (634 mg, 2.25 mmol) and 12M HCl (0.89 ml) in MeOH (20 ml) at 60°C. afforded the title compound (201 mg, 41%) as a white solid aftertrituration in DCM/Et₂O.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.91 (s, 1H), 4.36-4.15 (m, 5H), 3.83(s, 3H)

HPLCMS (Method M): [m/z]: 183.20 [M+H]⁺

Methyl2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3-oxazole-4-carboxylate(351)

A suspension of methyl 2-(azetidin-3-yl)-1,3-oxazole-4-carboxylatehydrochloride (350) (300 mg, 1.37 mmol),2-(3-chloropropyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazole(349) (758 mg, 2.33 mmol), DIPEA (837 μl, 4.8 mmol) and KI (228 mg, 1.37mmol) in DMF (10 ml) was stirred at room temperature for 7 d. Thereaction was quenched with saturated NaHCO₃ (aq) and extracted withEtOAc (3×50 ml). The combined organic extracts were washed with brine(4×50 ml), dried (Na₂SO₄), filtered and evaporated in vacuo.Purification by flash column chromatography (eluting with a gradient of40-100% EtOAc/heptane followed by 2-40% MeOH/EtOAc) afforded the titlecompound (329 mg, 46%, 91% purity) as a yellow residue.

HPLCMS (Method M): [m/z]: 471.15 [M+H]⁺

2-{1-[3-(1-{[2-(Trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3-oxazole-4-carboxylicacid (352)

In a similar fashion to general procedure 5,2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3-oxazole-4-carboxylate(351) (329 mg, 0.7 mmol) and LiOH (50 mg, 2.1 mmol) in THF (10 ml) andwater (10 ml) afforded the title compound (363 mg, 91%, 80% purity) as ayellow residue. The compound was used in the next step withoutpurification.

HPLCMS (Method M): [m/z]: 457.10 [M+H]⁺

N-[(3-fluoropyridin-2-yl)methyl]-2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3-oxazole-4-carboxamide(353)

In a similar manner to general procedure 6,2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3-oxazole-4-carboxylicacid (352) (363 mg, 0.64 mmol, 80% purity),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (152 mg, 0.76mmol), DIPEA (388 μl, 2.23 mmol) and HATU (290 mg, 0.76 mmol) in DCM (20ml) afforded the title compound (302 mg, 84%) as a pale yellow residueafter purification by flash column chromatography (eluting with agradient of 0-40% MeOH/DCM).

HPLCMS (Method M): [m/z]: 565.15 [M+H]⁺

2-{1-[3-(1H-1,3-Benzodiazol-2-yl)propyl]azetidin-3-yl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-4-carboxamide(Example Compound No. 233)

TFA (4 ml, 52.23 mmol) was added to a solution ofN-[(3-fluoropyridin-2-yl)methyl]-2-{1-[3-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,3-benzodiazol-2-yl)propyl]azetidin-3-yl}-1,3-oxazole-4-carboxamide(353) (300 mg, 0.53 mmol) in DCM (4 ml). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated in vacuo and the residue was dissolved in water basified bythe addition of 2M NaOH (aq). The mixture was then extracted with 4:1CHCl₃/IPA (4×50 ml). The combined organic extracts were dried (Na₂SO₄),filtered and evaporated in vacuo. The residue was dissolved in a minimumvolume of MeOH and loaded onto an SCX-2 cartridge (10 g). The cartridgewas rinsed with DCM, followed by MeOH, and eluted with 7N NH₃/MeOH. Thebasic eluent was evaporated under vacuum. Purification of the residue bybasic prep-HPLC afforded the title compound (75 mg, 33%) as a whitesolid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.37 (dt, J=4.6, 1.1 Hz, 1H), 8.33 (s,1H), 7.61 (ddd, J=9.8, 8.4, 1.2 Hz, 1H), 7.50 (s, 2H), 7.41 (dt, J=8.7,4.4 Hz, 1H), 7.23-7.17 (m, 2H), 4.77 (d, J=1.5 Hz, 2H), 3.93-3.84 (m,1H), 3.75 (t, J=8.0 Hz, 2H), 3.53 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.6 Hz,2H), 2.66-2.60 (m, 2H), 1.97-1.88 (m, 2H)

HPLCMS (Method B): [m/z]: 435.1 [M+H]⁺

General Scheme 28 Above3-{[(Tert-butoxy)carbonyl]amino}-3-methylbutanoic acid (360)

1M KOH (15.19 ml) was added to a mixture of 3-amino-3-methylbutanoicacid (1.78 g, 15.19 mmol) and Boc₂O (3.48 g, 15.95 mmol) in 1,4-dioxane(30 ml) and stirred at room temperature for 40 h. The solvent wasconcentrated and diluted with water (60 ml). 1M LiOH was added until pH13. The aqueous phase was extracted with Et₂O (3×30 ml), then the pHadjusted to 3 using 2M HCl and extracted with EtOAc (4×60 ml). Thecombined organic layers were washed with brine (30 ml), dried (Na₂SO₄),filtered and evaporated to give the title compound (2.13 g, 65%) as anoff-white solid. Compound will be used in the next step without furtherpurification.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.07 (s, 1H), 2.75 (s, 2H), 1.44 (s,9H), 1.40 (s, 6H)

3-{[(Tert-butoxy)carbonyl]amino}-2,2-dimethylpropanoic acid (361)

1M KOH (52.08 ml, 52.08 mmol) was added to a mixture of3-amino-2,2-dimethylpropanoic acid hydrochloride (4 g, 26.04 mmol) andBoc₂O (5.97 g, 27.34 mmol) in 1,4-dioxane (80 ml) and stirred at roomtemperature for 20 h. The solvent was concentrated and diluted withwater (50 ml). 1 M LiOH was added until pH 13. The aqueous phase wasextracted with Et₂O (3×50 ml), then the pH adjusted to 3 using 2M HCland extracted with EtOAc (4×50 ml). The combined organic layers werewashed with brine (50 ml), dried (Na₂SO₄), filtered and evaporated togive the title compound (5.38 g, 95%) as a white solid. Compound will beused in the next step without further purification.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.01 (s, 1H), 3.29-3.18 (m, 2H), 1.45(d, 9H), 1.23 (s, 6H)

Tert-butyl N-(1-carbamoyl-2-methylpropan-2-yl)carbamate (362)

TEA (2.82 ml, 20.27 mmol) was added to an ice-cooled (0° C.) solution of3-{[(tert-butoxy)carbonyl]amino}-3-methylbutanoic acid (360) (2.59 g,11.92 mmol) in THF (30 ml). The reaction mixture was stirred for 20 minbefore the addition of 2-methylpropyl carbonochloridate (2.78 ml, 17.88mmol) dropwise at 0° C. The reaction was stirred for 1 h before theaddition of 35% NH₃ (aqueous solution) (3.09 ml, 66.76 mmol) dropwiseand the reaction warmed to room temperature and stirred for 18 h.Saturated NaHCO₃ (50 ml) was added and the aqueous layer extracted withDCM (3×50 ml). The combined organic layers were dried (MgSO₄), filteredand evaporated to give a pale yellow oil (4.11 g). Purification by flashcolumn chromatography (eluting with a gradient of 0-10% MeOH-DCM) gavethe title compound (1.7 g, 55%, 84% purity) as a clear oil whichsolidified on standing.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.85 (br s, 1H), 5.39 (br s, 1H), 4.89(br s, 1H), 2.64 (s, 2H), 1.42 (s, 9H), 1.39 (s, 6H)

HPLCMS (Method A): [m/z]: 238.95 [M+Na]⁺

Tert-butyl N-(2-carbamoyl-2,2-dimethylethyl)carbamate (363)

TEA (5.73 ml, 41.08 mmol) was added to an ice-cooled (0° C.) solution of3-{[(tert-butoxy)carbonyl]amino}-2,2-dimethylpropanoic acid (361) (5.25g, 24.16 mmol) in THF (50 ml). The reaction was stirred for 20 min,before the addition of 2-methylpropyl carbonochloridate (4.7 ml, 36.3mmol) dropwise at 0° C. The reaction was stirred for 1 h before thedropwise addition of 35% NH₃ (aqueous solution) (7.48 ml, 135.31 mmol).The reaction mixture was warmed to room temperature and stirred for 22h. Saturated NaHCO₃ (100 ml) was added and the aqueous layer extractedwith DCM (3×150 ml). The combined organic layers were dried (MgSO₄),filtered and evaporated to give an off-white semi-solid (6.61 g).Purification by flash column chromatography (eluting with a gradient of0-10% MeOH/DCM) gave the title compound (3.7 g, 71%) as a white solid.

1H-NMR (CDCl₃, 250 MHz): d[ppm]=5.95 (s, 1H), 5.30 (s, 1H), 5.08 (s,1H), 3.25 (d, J=6.6 Hz, 2H), 1.43 (s, 9H), 1.21 (s, 6H)

HPLCMS (Method A): [m/z]: 239.10 [M+Na]⁺

Tert-butyl N-(1-carbamothioyl-2-methylpropan-2-yl)carbamate (364)

In a similar fashion to general procedure 11, Lawesson reagent (1.65 g,4.08 mmol) and tert-butyl N-(1-carbamoyl-2-methylpropan-2-yl)carbamate(362) (1.7 g, 6.6 mmol, 84% purity) in DCM (50 ml) at room temperaturefor 19 h gave the title compound (0.914 g, 60%) as a yellow oil afterpurification by flash column chromatography (eluting with a gradient of0-50% EtOAc/Heptane) which solidified on standing.

1H-NMR (MeOD, 250 MHz): d[ppm]=2.91 (s, 2H), 1.43 (s, 9H), 1.38 (s, 6H)

HPLCMS (Method A): [m/z]: 232.95 [M+H]⁺

Tert-butyl N-(2-carbamothioyl-2,2-dimethylethyl)carbamate (365)

In a similar fashion to general procedure 11, Lawesson reagent (3.29 g,8.14 mmol) and tert-butyl N-(2-carbamoyl-2,2-dimethylethyl)carbamate(363) (3.2 g, 14.8 mmol) in DCM (65 ml) at room temperature for 24 hgave the title compound (1.67 g, 49%) as a white solid afterpurification by flash column chromatography (eluting with a gradient of0-50% EtOAc-Heptane).

1H-NMR (MeOD, 250 MHz): d[ppm]=3.35 (s, 2H), 1.44 (s, 9H), 1.25 (s, 6H)

HPLCMS (Method A): [m/z]: 254.95 [M+Na]⁺

Ethyl2-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl)-1,3-thiazole-4-carboxylate(366)

In a similar fashion to general procedure 1, tert-butylN-(1-carbamothioyl-2-methylpropan-2-yl)carbamate (364) (0.91 g, 3.93mmol), ethyl 3-bromo-2-oxopropanoate (0.64 ml, 4.33 mmol) and CaCO₃(0.22 g, 2.16 mmol) in EtOH (10 ml) gave the title compound (0.285 g,19%) as an orange oil after purification by flash column chromatography(eluting with a gradient of 0-100% EtOAc/heptane).

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.42 (s, 1H), 4.29 (q, J=7.2 Hz, 2H),3.39 (s, 2H), 1.36 (s, 9H), 1.30 (d, J=7.0 Hz, 3H), 1.20 (s, 6H)

HPLCMS (Method A): [m/z]: 329.00 [M+H]⁺

Ethyl2-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-1,3-thiazole-4-carboxylate(367)

In a similar fashion to general procedure 1, tert-butylN-(2-carbamothioyl-2,2-dimethylethyl)carbamate (365) (1.67 g, 7.9 mmol),ethyl 3-bromo-2-oxopropanoate (1.2 ml, 7.9 mmol) and CaCO₃ (0.4 g, 3.95mmol) in EtOH (20 ml) was stirred at room temperature for 72 h. Thereaction was further treated with MgSO₄ (0.8 g) and CaCO₃ (0.4 g, 3.95mmol) and heated at 80° C. for 7 h. The reaction was cooled and thesolvent evaporated to give a residue which was partitioned taken up inEtOAc (50 ml) and washed with saturated NaHCO₃ (7 ml). The aqueous layerwas extracted with EtOAc (3×15 ml) and the combined organic layers weredried (MgSO₄), filtered and evaporated to give a brown oil (2.61 g). Theoil was dissolved in DCM (50 ml) and TEA (2.9 ml, 20.58 mmol) was addedfollowed by dropwise addition of di-tert-butyl dicarbonate (3.74 g,17.15 mmol) in DCM (20 ml). The reaction was stirred at room temperaturefor 22 h. The reaction mixture was diluted with DCM (10 ml) and theorganic layer was washed with water (20 ml), brine (20 ml), dried(MgSO₄), filtered and evaporated to give a brown oil (4.82 g).Purification by flash column chromatography (eluting with 0-50%EtOAc-heptane) gave the title compound (1.4 g, 36%) as a yellow oil.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.06 (s, 1H), 5.19 (br s, 1H), 4.40(q, J=7.1 Hz, 2H), 3.50 (br s, 2H), 1.44 (s, 6H), 1.42 (s, 9H)

HPLCMS (Method A): [m/z]: 329.00 [M+H]⁺

2-(2-{[(Tert-butoxy)carbonyl]amino}-2-methylpropyl)-1,3-thiazole-4-carboxylicacid (368)

In a similar fashion to general procedure 5, ethyl2-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl)-1,3-thiazole-4-carboxylate(366) (0.285 g, 0.867 mmol, 85% purity) and LiOH (88 mg, 3.67 mmol) inTHF (4 ml) and H₂O (2 ml) at room temperature for 5 h gave the titlecompound (0.215 g, 66%, 68% purity) as a dark yellow oil. Compound wasused in the next step without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.35 (s, 1H), 3.38 (s, 2H), 1.43 (s,9H), 1.21 (s, 6H)

HPLCMS (Method A): [m/z]: 301.00 [M+H]⁺

2-(1-{[(Tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-1,3-thiazole-4-carboxylicacid (369)

In a similar fashion to general procedure 5, ethyl2-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-1,3-thiazole-4-carboxylate(367) (1.4 g, 4.12 mmol) and LiOH (0.49 g, 20.6 mmol) in THF (20 ml) andwater (10 ml) at room temperature for 3 h gave the title compound (1.5g, 98%, 83% purity) as a yellow oil which solidified on standing. To beused without purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.32 (s, 1H), 6.98-6.88 (m, 1H), 3.18(d, J=6.5 Hz, 2H), 1.34 (s, 9H), 1.32 (s, 6H)

HPLCMS (Method A): [m/z]: 301.05 [M+H]⁺

Tert-butylN-[1-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-2-methylpropan-2-yl]carbamate(370)

In a similar fashion to general procedure 6,2-(2-{[(tert-butoxy)carbonyl]amino}-2-methylpropyl)-1,3-thiazole-4-carboxylicacid (368) (0.28 g, 0.63 mmol, 68% purity),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.20 g, 1.01mmol), HATU (0.4 g, 1.04 mmol) and DIPEA (0.4 ml, 2.29 mmol) in DMF (6ml) were stirred at room temperature for 2 h, gave the title compound(0.33 g, 84%, 72% purity) as a dark yellow oil after purification byflash column chromatography (eluting with a gradient of 0-100%EtOAc/heptane). To be used without further purification.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.58 (t, J=5.6 Hz, 1H), 8.39 (dt,J=4.7, 1.5 Hz, 1H), 8.19 (s, 1H), 7.78-7.63 (m, 1H), 7.47-7.35 (m, 1H),6.68 (s, 1H), 4.67 (dd, J=5.6, 1.3 Hz, 2H), 3.41 (s, 2H), 1.41 (s, 9H),1.23 (s, 6H)

HPLCMS (Method A): [m/z]: 409.05 [M+H]⁺

Tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-2-methylpropyl]carbamate(371)

In a similar fashion to general procedure 6,2-(1-{[(tert-butoxy)carbonyl]amino}-2-methylpropan-2-yl)-1,3-thiazole-4-carboxylicacid (369) (0.64 g, 1.73 mmol, 83% purity),(3-fluoropyridin-2-yl)methanamine dihydrochloride (A2) (0.41 g, 2.08mmol), HATU (0.79 g, 2.08 mmol) and DIPEA (0.99 ml, 5.71 mmol) in DCM (8ml) at room temperature for 17 h gave the title compound (1.78 g, 90%purity) after purification by flash column chromatography (eluting witha gradient of 0-100% EtOAc/heptane) as a yellow oil which solidified onstanding.

1H-NMR (DMSO-d6, 250 MHz): d[ppm]=8.71 (t, J=5.8 Hz, 1H), 8.43-8.33 (m,1H), 8.15 (s, 1H), 7.76-7.65 (m, 1H), 7.47-7.34 (m, 1H), 6.97 (t, J=6.3Hz, 1H), 4.67 (dd, J=5.8, 1.5 Hz, 2H), 3.25 (d, J=6.5 Hz, 2H), 1.34 (s,6H), 1.34 (s, 9H)

HPLCMS (Method A): [m/z]: 409.45 [M+H]⁺

2-(2-Amino-2-methylpropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide dihydrochloride (372)

In a similar fashion to general procedure 2, tert-butylN-[1-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-2-methylpropan-2-yl]carbamate(370) (0.33 g, 0.58 mmol, 72% purity) and 12M HCl (0.73 ml, 8.78 mmol)in MeOH (5 ml) at 50° C. for 2 h gave the title compound (0.26 g, 90%,76% purity) as a beige residue which was used in the next step withoutpurification.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.53 (dd, J=5.3, 1.0 Hz, 1H), 8.24 (s,1H), 8.16-8.06 (m, 1H), 7.82-7.73 (m, 1H), 4.91 (d, J=1.4 Hz, 2H), 3.42(s, 2H), 1.46 (s, 6H)

HPLCMS (Method A): [m/z]: 308.95 as the freebase [M+H]⁺

2-(1-Amino-2-methylpropan-2-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (373)

In a similar fashion to general procedure 2, tert-butylN-[2-(4-{[(3-fluoropyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)-2-methylpropyl]carbamate(371) (1.78 g, 3.93 mmol, 90% purity) and 12M HCl (6.61 ml, 79.3 mmol)in MeOH (30 ml) at room temperature for 70 h gave the title compound(1.54 g, 98%) as a brown foam. To be used without purification.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.49-8.44 (m, 1H), 8.24 (s, 1H),7.98-7.88 (m, 1H), 7.68-7.59 (m, 1H), 4.88 (d, J=1.5 Hz, 2H), 3.37 (s,2H), 1.58 (s, 6H)

HPLCMS (Method A): [m/z]: 309.00 as the freebase [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]-2-methylpropyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 231)

In a similar fashion to general procedure 3,2-(2-amino-2-methylpropyl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (372) (0.26 g, 0.52 mmol, 77% purity)1H-1,3-benzodiazole-2-carbaldehyde (0.106 g, 0.73 mmol), DIPEA (0.36 ml,2.09 mmol) in MeOH (5 ml) at 50° C. for 3.5 h, followed by the additionof NaBH₄ (35 mg, 0.93 mmol) at 00, gave the title compound (0.054 g,24%) as a cream solid after purification by kp-NH flash columnchromatography (eluting with a gradient of 0-6% MeOH/DCM) followed byflash column chromatography (eluting with a gradient of 0-20% MeOH/DCM).

1H-NMR (MeOD, 500 MHz): d[ppm]=8.14-8.12 (m, 1H), 8.11 (s, 1H),7.52-7.46 (m, 1H), 7.46-7.41 (m, 2H), 7.27-7.22 (m, 1H), 7.17-7.12 (m,2H), 4.70 (d, J=1.5 Hz, 2H), 4.21 (s, 2H), 3.27 (s, 2H), 1.25 (s, 6H)

HPLCMS (Method C): [m/z]: 439.1 [M+H]⁺

2-(1-{[2-(1H-1,3-benzodiazol-2-yl)ethyl]amino}-2-methylpropan-2-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 242)

In a similar fashion to general procedure 8,2-(1-amino-2-methylpropan-2-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidedihydrochloride (373) (1.54 g, 3.85 mmol),N-(2-nitrophenyl)prop-2-enamide (D) (0.81 g, 4.24 mmol) and DBU (1.73ml, 11.56 mmol) in MeCN (35 ml) at room temperature for 18 h gave amixture of mono:bis-alkylated adducts (3.7:1) (2.23 g) as an orange oil.This was further reacted with iron powder (0.86 g) in AcOH (10 ml) at75° C. for 0.5 h to give the title compound (0.29 g, 17%) as anoff-white solid after purification by flash column chromatography(eluting with a gradient of 0-40% MeOH/DCM) followed by kp-NH columnchromatography (eluting with a gradient of 0-5% MeOH/DCM) and basicprep-HPLC.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.30-8.25 (m, 1H), 7.97 (s, 1H),7.57-7.52 (m, 1H), 7.43-7.35 (m, 2H), 7.34-7.29 (m, 1H), 7.18-7.13 (m,2H), 4.65 (d, J=1.5 Hz, 2H), 3.09-3.05 (m, 2H), 3.05-3.01 (m, 2H), 2.98(s, 2H), 1.46 (s, 6H)

HPLCMS (Method C): [m/z]: 453.1 [M+H]⁺

General Scheme 1 AboveN-(1H-1,3-Benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(441)

In a similar fashion to general procedure 6,2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)[(tert-butoxy)carbonyl]amino]ethyl}-1,3-thiazole-4-carboxylicacid (8) (2.75 g, 6.49 mmol), 1-(3-methylpyridin-2-yl)methanamine (1.19g, 9.74 mmol), DIPEA (3.39 ml, 19.47 mmol) and HATU (4.94 g, 12.98 mmol)in DMF (50 ml) for 16 h, gave the title compound (1.7 g, 51%) as anyellow foam after purification by flash column chromatography (Kp-NH,eluting with a gradient of 20-100% EtOAc/heptane) followed byazeotroping with heptane.

1H-NMR (MeOD, 250 MHz): d[ppm]=8.32 (d, J=4.4 Hz, 1H), 8.09 (s, 1H),7.63 (d, J=7.6 Hz, 1H), 7.53 (s, 2H), 7.30-7.14 (m, 3H), 4.74 (s, 2H),4.69 (s, 2H), 3.86 (s, 2H), 3.34 (s, 3H), 2.40 (s, 3H), 1.40 (s, 10H)

HPLCMS (Method C): [m/z]: 507.1 [M+H]⁺

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-methylpyridin-2-yl)methyl]-1,3-thiazole-4-carboxamidetrihydrochloride (Example Compound No. 55)

In a similar fashion to general procedure 2, tert-butylN-(1H-1,3-benzodiazol-2-ylmethyl)-N-[2-(4-{[(3-methylpyridin-2-yl)methyl]carbamoyl}-1,3-thiazol-2-yl)ethyl]carbamate(441) (1.7 g, 3.36 mmol) and 4M HCl/dioxane (8.4 ml) in dioxane (30 ml)at room temperature for 16 h gave the title compound (1.09 g, 63%) as awhite solid after trituration from Et₂O (2×30 ml), DCM (2×20 ml) andEt₂O (2×30 ml) followed by recrystallisation from DCM/MeOH and Heptane.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=10.29 (s, 1H), 9.56 (t, J=5.6 Hz, 1H),8.64-8.57 (m, 1H), 8.37 (d, J=7.7 Hz, 1H), 8.29 (s, 1H), 7.85 (dd,J=7.8, 5.8 Hz, 1H), 7.73 (dt, J=6.6, 3.3 Hz, 2H), 7.41 (dt, J=6.1, 3.3Hz, 2H), 4.85 (d, J=5.7 Hz, 3H), 4.74 (s, 2H), 3.64 (dt, J=35.5, 7.0 Hz,5H), 2.50 (s, 3H)

HPLCMS (Method C): [m/z]: 407.05 [M+H]⁺

General Scheme 41 Above Tert-butyl3-[(pyridin-2-ylmethyl)carbamoyl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-6-carboxylate(449)

In a similar fashion to general procedure 6,6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxylicacid (220 mg, 0.77 mmol), 1-(pyridin-2-yl)methanamine (88 μl, 0.85mmol), DIPEA (407 μl, 2.33 mmol) and HATU (443 mg, 1.17 mmol) in DCM (12ml) at room temperature for 1 h gave the title compound (466 mg) as ayellow oil after purification by flash column chromatography (elutingwith a gradient 50-100% EtOAc/heptane).

1H-NMR (CDCl₃, 500 MHz): d[ppm]=8.55 (d, J=4.8 Hz, 1H), 7.68 (td, J=7.7,1.8 Hz, 1H), 7.64 (s, 1H), 7.31 (d, J=7.8 Hz, 1H), 7.22 (dd, J=7.2, 5.2Hz, 1H), 4.70 (d, J=4.8 Hz, 2H), 4.62 (s, 2H), 3.76-3.61 (m, 2H), 2.99(s, 2H), 1.48 (s, 9H), 1.44 (d, J=6.6 Hz, 1H)

HPLCMS (Method E): [m/z]: 374.05 [M+H]⁺

N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide(450)

In a similar fashion to general procedure 2, tert-butyl3-[(pyridin-2-ylmethyl)carbamoyl]-4H,5H,6H,7H-thieno[2,3-c]pyridine-6-carboxylate(449) (466 mg, 1.09 mmol) and TFA (940 μl) in DCM (5 ml) at roomtemperature for 16 h gave the title compound (130 mg, 44%) as an yellowoil. The compound was used in the next step without purification.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.49 (d, J=4.3 Hz, 1H), 7.92 (s, 1H),7.82 (td, J=7.7, 1.8 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.37-7.27 (m, 1H),4.59 (s, 2H), 4.16 (s, 2H), 3.21 (t, J=6.0 Hz, 2H), 3.01 (t, J=6.0 Hz,2H)

HPLCMS (Method E): [m/z]: 273.95 [M+H]⁺

6-(1H-1,3-Benzodiazol-2-ylmethyl)-N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide(Example Compound No. 48)

In a similar fashion to general procedure 7,N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide(450) (65 mg, 0.24 mmol), K₂COO₃ (49 mg, 0.36 mmol) and2-(chloromethyl)-1H-benzimidazole (44 mg, 0.26 mmol) in acetone (3 ml)at room temperature for 72 h, gave the title compound (25 mg, 26%) as apale yellow solid after purification flash column chromatography (kp-NH,eluting with a gradient of 0-10% MeOH/DCM) followed by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.36 (s, 1H), 8.78 (t, J=6.0 Hz, 1H),8.50 (d, J=4.7 Hz, 1H), 7.95 (s, 1H), 7.76 (td, J=7.7, 1.7 Hz, 1H), 7.49(s, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.29-7.23 (m, 1H), 7.14 (dd, J=5.9, 3.1Hz, 2H), 4.49 (d, J=6.0 Hz, 2H), 3.93 (s, 2H), 3.73 (s, 2H), 2.89 (d,J=5.5 Hz, 2H), 2.79 (t, J=5.7 Hz, 2H)

HPLCMS (Method D): [m/z]: 404.2 [M+H]⁺

6-[2-(1H-1,3-Benzodiazol-2-yl)ethyl]-N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide(Example Compound No. 49)

In a similar fashion to general procedure 7,N-(pyridin-2-ylmethyl)-4H,5H,6H,7H-thieno[2,3-c]pyridine-3-carboxamide(450) (65 mg, 0.24 mmol), K₂COO₃ (49 mg, 0.36 mmol) and2-(2-chloroethyl)-1H-benzimidazole (47 mg, 0.26 mmol) in acetone (3 ml)at room temperature for 24 h, followed by the addition of DMF (5 ml),NaI (39 mg, 0.26 mmol), DIPEA (0.16 ml, 0.95 mmol) and2-(2-chloroethyl)-1H-benzimidazole (94 mg, 0.52 mmol) at roomtemperature for 72 h, gave the title compound (9 mg, 9%) as an orangesolid after purification by basic prep-HPLC.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=12.17 (s, 1H), 8.75 (t, J=6.0 Hz, 1H),8.50 (d, J=4.2 Hz, 1H), 7.94 (s, 1H), 7.75 (td, J=7.7, 1.8 Hz, 1H), 7.46(s, 2H), 7.31 (d, J=7.8 Hz, 1H), 7.28-7.23 (m, 1H), 7.10 (dd, J=6.0, 3.1Hz, 2H), 4.48 (d, J=6.0 Hz, 2H), 3.71 (s, 2H), 3.05 (t, J=7.2 Hz, 2H),2.96 (t, J=7.2 Hz, 2H), 2.82 (d, J=5.3 Hz, 2H), 2.75 (t, J=5.7 Hz, 2H)

HPLCMS (Method B): [m/z]: 418.2 [M+H]⁺

General Scheme 42 Above2-{2-[N-(1H-1,3-benzodiazol-2-ylmethyl)-2-bromoacetamido]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(451)

2-{2-[(1H-1,3-benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 40) (150 mg, 0.37 mmol) and TEA (127 μl, 0.91mmol) were dissolved in DCM (10 ml) and bromoacetyl chloride (61 μl,0.73 mmol) was added dropwise. The mixture was stirred at roomtemperature for 15 mins, then quenched with saturated NaHCO₃ (aq) (20ml) and extracted with DCM (3×30 ml) and 4:1 chloroform/IPA (30 ml). Thecombined organic extracts were dried (Na₂SO₄) and evaporated in vacuo.Purification by flash column chromatography (eluting with a gradient of0-5% MeOH/DCM) afforded the title compound (224 mg, 82% purity) as abrown residue. Compound was used in the next step without furtherpurification.

HPLCMS (Method M): [m/z]: 530.85/532.85 [M+H]⁺

N-[(3-fluoropyridin-2-yl)methyl]-2-(2-{12-oxo-1,8,11-triazatricyclo[7.4.0.0²,7]trideca-2(7),3,5,8-tetraen-11-yl}ethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 275)

2-{2-[N-(1H-1,3-benzodiazol-2-ylmethyl)-2-bromoacetamido]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(451) (220 mg, 0.41 mmol, 82% purity) was dissolved in THF (10 ml) andNaH (60%, 50 mg, 1.24 mmol) was added. The mixture was stirred at roomtemperature for 10 mins. The reaction was quenched with saturated NaHCO₃(aq) (20 ml) and extracted with DCM (3×20 ml) and 4:1 chloroform/IPA (20ml). The combined organic extracts were dried (Na₂SO₄) and evaporated invacuo. Purification by basic prep-HPLC afforded the title compound (15mg, 8%) as an off-white solid.

1H-NMR (DMSO-d6, 500 MHz): d[ppm]=8.65 (t, J=5.6 Hz, 1H), 8.36-8.32 (m,1H), 8.18 (s, 1H), 7.71-7.64 (m, 1H), 7.61 (dt, J=5.4, 3.4 Hz, 1H),7.56-7.51 (m, 1H), 7.40-7.34 (m, 1H), 7.26-7.21 (m, 2H), 4.91 (s, 2H),4.88 (s, 2H), 4.63-4.57 (m, 2H), 3.93 (t, J=7.2 Hz, 2H), 3.42 (t, J=7.2Hz, 2H)

HPLCMS (Method B): [m/z]: 451.2 [M+H]⁺

N-[(3-fluoropyridin-2-yl)methyl]-2-(2-{1,8,11-triazatricyclo[7.4.0.0²,7]trideca-2(7),3,5,8-tetraen-11-yl}ethyl)-1,3-thiazole-4-carboxamide(Example Compound No. 276)

2-{2-[(1H-1,3-Benzodiazol-2-ylmethyl)amino]ethyl}-N-[(3-fluoropyridin-2-yl)methyl]-1,3-thiazole-4-carboxamide(Example Compound No. 40) (150 mg, 0.37 mmol) and TEA (509 μl, 3.65mmol) were combined in DMF (4 ml) and 1,2-dibromoethane (315 μl, 3.65mmol) was added. The mixture was heated at 100° C. for 40 mins, thencooled to room temperature and quenched with saturated NaHCO₃ (aq). Themixture was extracted with DCM (3×50 ml) and the combined organicextracts were washed with aqueous LiCl (2M, 50 ml), dried (Na₂SO₄) andevaporated in vacuo. Purification by basic prep-HPLC followed by flashcolumn chromatography (eluting with a gradient 0-4% MeOH/DCM) affordedthe title compound (45 mg, 28%) as a pale yellow solid.

1H-NMR (MeOD, 500 MHz): d[ppm]=8.37 (dt, J=4.7, 1.2 Hz, 1H), 8.09 (s,1H), 7.64-7.57 (m, 2H), 7.51-7.46 (m, 1H), 7.42-7.37 (m, 1H), 7.32-7.26(m, 2H), 4.80 (d, J=1.6 Hz, 2H), 4.23 (t, J=5.5 Hz, 2H), 4.04 (s, 2H),3.41 (t, J=6.8 Hz, 2H), 3.25-3.20 (m, 2H), 3.16 (t, J=6.8 Hz, 2H)

HPLCMS (Method B): [m/z]: 437.1 [M+H]⁺

tert-butyl(2-(4-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)ethyl)carbamate(452)

1-(2-((tert-butoxycarbonyl)amino)ethyl)-1H-1,2,3-triazole-4-carboxylicacid (commercial available) (2.0 g, 7.8 mmol) in 50 ml DCM was cooled to−5° C. and N-methylmorpholine (0.94 ml, 8.6 mmol) and ethylchloroformatewere added to the mixture. During the addition temperature was keptbelow 0° C. and after addition the mixture was stirred at 0° C. for onehour. A second portion of N-methylmorpholine (2.7 ml, 24.2 mmol) and(3-Fluoropyridin-2-yl)methanamine dihydrochloride (A2) were added. Thereaction was allowed to warm to room temperature and stirred overnight.50 ml of water were added to the reaction and extracted with DCM. Theorganic phase was dried (Na2SO4), filtered and concentrated in vacuo tothe crude product which was purified by flash column chromatography togive the title compound (2.1 g, 74%).

1H-NMR (DMSO, 400 MHz): d[ppm]=8.82 (t, 1H), 8.50 (s, 1H), 8.38 (d, 1H),7.70 (m, 1H), 7.40 (m, 1H), 7.01 (s, 1H), 4.65 (d, 2H), 4.46 (m, 2H),3.39 (m, 2H), 1.40-1.24 (m, 9H)

1-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamidehydrochloride (453)

16 ml conc. HCl was added to a solution of tert-butyl(2-(4-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-1H-1,2,3-triazol-1-yl)ethyl)carbamate(452) (2.00 g, 5.49 mmol) in 100 ml methanol and stirred at roomtemperature for 2 h. The mixture was evaporated in vacuo to afford thetitle compound (1.74 g, 99%) as a white solid.

1H-NMR (DMSO, 400 MHz): d[ppm]=8.99 (t, 1H), 8.73 (s, 1H), 8.51 (s, 3H),8.45 (d, 1H), 7.87 (m, 1H), 7.53 (m, 1H), 4.78 (m, 2H), 4.71 (d, 2H),3.37 (m, 2H)

N-((3-fluoropyridin-2-yl)methyl)-1-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-1H-1,2,3-triazole-4-carboxamide(454)

1-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamidehydrochloride (453) (4.46 g, 13.2 mmol) and DBU (10.1 g, 66.1 mmol) weresuspended in 120 ml acetonitrile. N-(2-Nitrophenyl)prop-2-enamide (D)(2.54 g, 13.2 mmol) in 10 ml acetonitrile was added dropwise to thereaction mixture within 1 h and stirred at room temperature overnight.The reaction was evaporated to dryness and redissolved in 100 ml DCM. 50ml water were added and extracted with DCM. The organic phases was dried(Na₂SO₄), filtered and concentrated in vacuo to the crude product whichwas purified by flash column chromatography to give the title compound(2.1 g, 35%).

1H-NMR (DMSO, 400 MHz): d[ppm]=10.55 (s, 1H), 8.78 (t, 1H), 8.57 (s,1H), 8.38 (d, 1H), 7.93 (m, 1H), 7.76-7.62 (m, 3H), 7.40 (m, 1H), 7.32(m, 1H), 4.65 (d, 2H), 4.50 (m, 2H), 3.02 (t, 2H), 2.81 (t, 2H), 2.51(m, 2H)

1-(2-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxamide(Example Compound No. 277)

N-((3-fluoropyridin-2-yl)methyl)-1-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-1H-1,2,3-triazole-4-carboxamide(454) (900 mg, 1.97 mmol) and iron powder (335 mg, 5.92 mmol) weresuspended in 10 ml acetic acid and stirred under nitrogen at 80° C. for2 h. The reaction mixture was evaporated to dryness and the residuetreated with 60 ml chloroform/isopropanpol (1:4). The pH was adjusted to11 by addition of 1N NaOH and the phases were separated. Afterextraction of the aqueous phase with chloroform the combined organicphases were dried (Na₂SO₄), filtered and concentrated in vacuo to thecrude product which was purified by flash column chromatography to givethe title compound (430 mg, 53%).

1H-NMR (d4-methanol, 400 MHz): d[ppm]=8.40 (s, 1H), 8.38 (m, 1H),7.63-7.58 (m, 1H), 7.50-7.45 (m, 2H), 7.41-7.36 (m, 1H), 7.18-12 (m,2H), 4.78 (d, 2H), 4.56 (m, 2H), 3.16 (t, 2H), 3.10-3.0 (m, 4H)

5-(2-((tert-butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxylicacid

To a round bottomed flask was added ethyl5-(2-((tert-butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxylate(4 g, 14.06 mmol), THF (80 ml) and water (20 ml) with stirring at roomtemperature. Lithium hydroxide (1 g, 41.75 mmol) was then added to thesolution and the reaction mixture stirred at room temperature for 2 hr.The reaction mixture was then acidified to pH2.8 (using aq. 32% HCl),extracted with ethyl acetate (3×80 ml), dried (Na2SO4), filtered andevaporated to afford the title compound as a brown oil (2.95 g), whichwas used without purification.

tert-butyl(2-(3-((pyridin-2-ylmethyl)carbamoyl)-1,3,4-oxadiazol-5-yl)ethyl)carbamate

To a solution of5-(2-((tert-butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxylicacid (2.95 g, 11.47 mmol) in 100 ml dichloromethane at 0° C. was added4-methylmorpholine (2.8 ml, 25.47 mmol) and ethylchloroformate (1 ml,10.46 mmol). After 60 min stirring at 0° C., 2-picolylamine (1.7 ml,16.82) was added and the reaction mixture was stirred 2 h at RT. Thereaction mixture washed with water (100 ml), dried (Na2SO4), filteredand evaporated. The crude product was purified using a 100 g SNAP Ultracolumn (eluted with a gradient of 0 to 100% ethylacetate in petrolether)to give a pale brown oil (2.29 g, 6.6 mmol, 58%).

¹H NMR (400 MHz, CDCl3): δ 8.5 (s, 1H), 8.1 (m, 2H), 7.7 (m, 1H), 7.3(m, 2H), 6.8 (s, 1H), 4.6 (s, 2H), 3.4 (m, 2H), 2.5 (m, 2H), 1.4 (s,9H).

5-(2-aminoethyl)-N-(pyridine-2-ylmethyl)-1,2,4-oxadiazole-3-carboxamidedihydrochloride

To a solution of tert-butyl(2-(3-((pyridin-2-ylmethyl)carbamoyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate(2.41 g, 6.94 mmol) in dioxane (25 ml) and was added 4 M HCl in dioxane(25 ml). After stirring at RT for 2 hours the reaction mixture wasevaporated to afford the title compound as a brown oil (2.83 g), whichwas used without purification.

5-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3-carboxamide

In a round bottomed flask,5-(2-aminoethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3-carboxamidedihydrochloride (3.48 g, 9.76 mmol) was suspended in acetonitrile (100ml) under nitrogen and 1,8-diazabicycloundec-7-ene (DBU) (7.1 ml, 47.48mmol, 4.9 eq) was added dropwise followed byN-(2-nitrophenyl)prop-2-enamide (1.9 g, 9.89). The reaction was stirredat room temperature overnight, then evaporated, diluted with 100 mldichloromethane, washed with 50 ml water, dried (Na₂SO₄), filtered andevaporated. The crude product was purified using a 100 g SNAP Ultracolumn (eluted each time with a gradient of 0 to 25% methanol indichloromethane) to give a pale brown oil (0.74 g, 1.7 mmol, 17%).

¹H NMR (400 MHz, CDCl3): δ 8.5 (s, 1H), 8.1 (m, 2H), 7.8 (m, 1H), 7.6(m, 1H), 7.3 (m, 3H), 4.4 (s, 2H), 3.1 (m, 4H), 2.7 (m, 2H), 2.5 (m,2H).

5-(2-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3-carboxamide(Example Compound No. 278)

5-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-N-(pyridin-2-ylmethyl)-1,2,4-oxadiazole-3-carboxamide(0.74 g, 1.68 mmol) was dissolved in acetic acid (5 ml) under nitrogenand iron powder (0.3 g) was added. The reaction mixture was heated to80° C. for 3 hours. After cooling at RT, toluene (50 ml) was added andthe mixture evaporated. A mixture of chloroform:IPA (4:1, 40 ml) wasadded, the reaction mixture cooled to 0° C., basified using 6M NaOHsolution to pH 10-12, filtered, dried (Na₂SO₄), filtered and evaporated.The crude product was purified using a 50 g SNAP KP-Sil column (elutedwith a gradient of 0 to 25% methanol in dichloromethane) to give a palebrown oil (0.31 g, 0.8 mmol, 47%).

¹H NMR (400 MHz, MeOD): δ 8.4 (s, 1H), 7.9 (s, 1H), 7.7 (m, 2H), 7.3 (m,1H), 7.2 (m, 1H), 7.1 (m, 2H), 4.4 (s, 2H), 3.1 (m, 4H), 2.9 (m, 2H),2.5 (m, 2H).

tert-butyl(2-(3-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate

To a solution of5-(2-((tert-butoxycarbonyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxylicacid (8.16 g, 31.72 mmol) in 400 ml dichloromethane at −5° C. was added4-methylmorpholine (20 ml, 182 mmol) and ethylchloroformate (2.7 ml,28.24 mmol). After 60 min stirring at −5° C.,(3-fluoropyridin-2-yl)methanamine dihydrochloride (9.50, 47.73) wasadded and the reaction mixture was stirred 2 h at RT. The reactionmixture washed with water (400 ml), dried (Na2SO4), filtered andevaporated. The crude product was purified using a 100 g SNAP Ultracolumn (eluted with a gradient of 0 to 100% ethylacetate in petrolether)to give a pale brown oil (4.15 g, 11.4 mmol, 36%).

¹H NMR (400 MHz, CDCl3): δ 8.3 (s, 1H), 7.4 (m, 1H), 7.3 (m, 1H), 6.9(s, 1H), 4.6 (s, 2H), 3.4 (m, 2H), 2.5 (m, 2H), 1.4 (s, 9H).

5-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamidedihydrochloride

To a solution of tert-butyl(2-(3-(((3-fluoropyridin-2-yl)methyl)carbamoyl)-1,2,4-oxadiazol-5-yl)ethyl)carbamate(4.23 g, 11.58 mmol) in dioxane (50 ml) and was added 4 M HCl in dioxane(50 ml). After stirring at RT for 3 hours the reaction mixture wasevaporated to afford the title compound as a brown oil (3.78 g), whichwas used without purification.

N-((3-fluoropyridin-2-yl)methyl)-5-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxamide

In a round bottomed flask,5-(2-aminoethyl)-N-((3-fluoropyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamidedihydrochloride (3.72 g, 9.93 mmol) was suspended in acetonitrile (100ml) under nitrogen and 1,8-diazabicycloundec-7-ene (DBU) (7.42 ml, 49.65mmol, 5 eq) was added dropwise followed byN-(2-nitrophenyl)prop-2-enamide (1.91 g, 9.93). The reaction was stirredat room temperature overnight, then evaporated, diluted with 100 mldichloromethane, washed with 50 ml water, dried (Na₂SO₄), filtered andevaporated. The crude product was purified using a 100 g SNAP KP-Silcolumn (eluted with a gradient of 0 to 25% methanol in dichloromethane)to give a pale brown oil (1.7 g, 3.7 mmol, 37%).

¹H NMR (400 MHz, MeOD): δ 8.3 (s, 1H), 8.1 (m, 2H), 7.6 (m, 1H), 7.5 (m,1H), 7.3 (m, 2H), 4.5 (s, 2H), 3.0 (m, 4H), 2.7 (m, 2H), 2.5 (m, 2H).

5-(2-((2-(1H-benzo[d]imidazol-2-yl)ethyl)amino)ethyl)-N-((3-fluoropyridin-2-yl)methyl)-1,2,4-oxadiazole-3-carboxamide(Example Compound No. 279)

N-((3-fluoropyridin-2-yl)methyl)-5-(2-((3-((2-nitrophenyl)amino)-3-oxopropyl)amino)ethyl)-1,2,4-oxadiazole-3-carboxamide(2.3 g, 5.03 mmol) was dissolved in acetic acid (20 ml) under nitrogenand iron powder (1.4 g) was added. The reaction mixture was heated to80° C. for 3 hours. After cooling at RT, toluene (200 ml) was added andthe mixture evaporated. A mixture of chloroform: IPA (4:1, 100 ml) wasadded, the reaction mixture cooled to 0° C., basified using 6M NaOHsolution to pH 10-12, filtered, dried (Na₂SO₄), filtered and evaporated.The crude product was purified using a 100 g SNAP KP-Sil column (elutedwith a gradient of 0 to 25% methanol in dichloromethane) to give a palebrown oil (1.51 g, 3.7 mmol, 74%).

¹H NMR (400 MHz, MeOD): δ 8.2 (s, 1H), 7.5 (m, 3H), 7.3 (m, 1H), 7.1 (m,2H), 4.5 (s, 2H), 3.1 (m, 4H), 2.9 (m, 2H), 2.4 (m, 2H).

2-(1-((1H-benzo[d]imidazol-2-yl)methyl)azetidin-3-yl)-N-((3-fluoropyridin-2-yl)methyl)oxazole-5-carboxamide(Example Compound No. 280)

In a round bottomed flask,2-(azetidin-3-yl)-N-[(3-fluoropyridin-2-yl)methyl]-1,3-oxazole-5-carboxamidedihydrochloride (similar starting compound as in the preparation ofExample Compound No. 2 above) (4 g, 11.5 mmol) was diluted indichloromethane (1600 ml) under nitrogen and diisopropylethylamine (20ml, 115 mmol, 11 eq) was added dropwise. The reaction stirred for 10 minat RT and then 1H-benzo[d]imidazole-2-carbaldehyde (2 g, 13.7 mmol, 1.3eq) was added. The reaction stirred at RT for 18 h and then sodiumtriacetoxyborohydride (5 g, 23.6 mmol, 2.3 eq) added and the reactionstirred at RT for 18 h. The reaction mixture washed with water (1000ml), separated, dried (MgSO4), filtered and evaporated. The crudeproduct was purified using a 100 g SNAP Ultra column and then a 55 gSNAP NH column (eluted each time with a gradient of 0 to 25% methanol indichloromethane) to give a pale brown oil (1.34 g, 3.3 mmol, 29%).

¹H NMR (400 MHz, CDCl3): δ 7.99 (m, 1H), 7.51 (m, 1H), 7.15 (m, 2H),7.01 (m, 1H), 6.88 (m, 1H), 6.81 (m, 2H), 4.4 (s, 2H), 3.6 (2H), 3.42(m, 1H), 3.35 (m, 2H), 3.28 (m, 2H).

MS (ESI+): m/z 407 [M+H]⁺.

FURTHER EMBODIMENTS OF THE INVENTION

1. Compounds according to formula (I)

whereinR¹ and R² are the same or different and are independently selected fromthe group consisting of

-   -   hydrogen,    -   optionally substituted alkyl,    -   optionally substituted aryl,    -   optionally substituted heteroaryl, or    -   R¹ and R² together with the nitrogen atom to which they are        bonded form an optionally substituted 3- to 6-membered ring,        which may optionally contain further heteroatoms;

X is O or S;

Y is hydrogen, optionally substituted alkyl or halogen,

A¹ is

-   -   optionally substituted alkanediyl;

A² is

-   -   optionally substituted alkanediyl,    -   a direct bond, or    -   a sulfonyl group;

R³ is

-   -   hydrogen, or    -   optionally substituted alkyl; or        A¹ and R³ together with the nitrogen atom to which they are        bonded form an optionally substituted 4- to 6-membered aliphatic        mono- or bicyclic ring; or        R³ and A² together with the nitrogen atom to which they are        bonded form an optionally substituted 4- to 7-membered aliphatic        ring;        and

Ar is

-   -   optionally substituted aryl,    -   optionally substituted monocyclic heteroaryl, or    -   optionally substituted bicyclic heteroaryl, which may be fused        with a ring formed by R³ and A² together with the nitrogen atom        to which they are bonded;        or pharmaceutically acceptable salts thereof.        2. Compounds according to embodiment 1, wherein

-   R¹ and R² are the same or different and are independently selected    from the group consisting of    -   hydrogen,    -   optionally substituted alkyl, or    -   R¹ and R² together with the nitrogen atom to which they are        bonded form and optionally substituted 3- to 6-membered ring,        which may optionally contain further heteroatoms;

-   X is O or S;

-   Y is hydrogen or C₁-C₃-alkyl, such as preferably hydrogen or methyl;

-   A¹ is optionally substituted alkanediyl;

-   A² is    -   optionally substituted alkanediyl, or    -   a direct bond;

-   R³ is    -   hydrogen, or    -   C₁-C₃-alkyl; or

-   A¹ and R³ together with the nitrogen atom to which they are bonded    form an optionally substituted 4-membered aliphatic monocyclic ring;    or

-   R³ and A² together with the nitrogen atom to which they are bonded    form an optionally substituted 4- to 7-membered aliphatic ring; and

-   Ar is optionally substituted bicyclic heteroaryl.    3. Compounds according to embodiment 1 or 2, wherein    at least one of R¹ and R² is a linear, branched or cyclic alkyl    group, which is substituted with a cyclic group “Cycl”, designated    as R^(2*), forming compounds according to formula (III)

whereinCycl is selected from

-   -   optionally substituted aryl, and    -   optionally substituted heteroaryl,        n is an integer of 1 to 3;        the remaining of R¹ or R², designated as R^(1*), is selected        from    -   hydrogen, and    -   optionally substituted alkyl, and        X, Y, R³, A¹, A² and Ar have the meaning as defined in the        preceding embodiments;        or pharmaceutically acceptable salts thereof.        4. Compounds according to any one of the preceding embodiments,        wherein the compounds are defined by

formula (IIIa)

or

formula (IIIb)

with Het-1 being

-   -   an optionally substituted, optionally fused 5- to 6-membered        heteroaryl, or    -   an optionally substituted 5- or 6-membered aliphatic        heterocyclyl, preferably a 6-membered aliphatic heterocyclyl,        which contain 1 or 2 identical or different heteroatoms selected        from the group consisting of N, O and S, preferably N;        and wherein in each case n is an integer of 1 to 3;        the remaining of R¹ or R², designated as R^(1*), is selected        from    -   hydrogen, and    -   optionally substituted alkyl; and        X, Y, R³, A¹, A² and Ar have the meaning as defined in the        preceding embodiments;        or pharmaceutically acceptable salts thereof.        5. Compounds according to any one of the preceding embodiments,        wherein the compounds are defined by

formula (IIIb-c)

formula (IIIb-d)

and

formula (IIIb-e)

wherein the pyrimidinyl, pyridazinyl and pyridinyl ring each may carry 1to 3, preferably 1 or 2 further substituents;and wherein in each case n is an integer of 1 to 3;the remaining of R¹ or R², designated as R^(1*), is selected from

-   -   hydrogen, and    -   optionally substituted alkyl; and        X, Y, R³, A¹, A² and Ar have the meaning as defined in the        preceding embodiments;        or pharmaceutically acceptable salts thereof.        6. Compounds according to any one of the preceding embodiments,        wherein the compounds are defined by

formula (IIIb-f)

wherein R⁵ indicates 1 to 3, preferably 1 or 2 optional substituents,which are preferably selected from C₁-C₃-alkyl and halogen, such as inparticular compounds of

formula (IIIb-g)

wherein R⁵ is preferably selected from C₁-C₃-alkyl and halogen, such aspreferably F;and wherein in each case n is an integer of 1 to 3;the remaining of R¹ or R², designated as R^(1*), is selected from

-   -   hydrogen, and    -   optionally substituted alkyl; and        X, Y, R³, A¹, A² and Ar have the meaning as defined in the        preceding embodiments;        or pharmaceutically acceptable salts thereof.        7. Compounds according to any one of the preceding embodiments,        wherein Ar is an optionally substituted mono- or bicyclic        heteroaryl, forming compounds according to formula (IV)

with Het-2 being

-   -   an optionally substituted, 5- or 6-membered monocyclic        heteroaryl, or    -   an optionally substituted bicyclic heteroaryl, which may be        fused with a ring formed by R³ and A² together with the nitrogen        atom to which they are bonded;        and wherein X, Y, R³, A¹, A² and Ar have the meaning as defined        in any one of the preceding embodiments;        or pharmaceutically acceptable salts thereof.        8. Compounds according to any one of the preceding claims, which        are defined by

formula (IVc)

with

-   -   both Y² being C or    -   one Y² being N and one Y² being C,        such as in particular compounds according to formula (IVd)

wherein in each case the bicyclic heteroaryl ring of Het-2 may carry 1to 3 substituents, preferably 1 or 2 substituents; and wherein thebicyclic heteroaryl ring of Het-2 of formula (IVc) or (IVd), may befused with a ring formed by R³ and A² together with the nitrogen atom towhich they are bonded, and wherein in each case R¹, R², X, Y, R³, A¹ andA² have the meaning as defined in the preceding embodiments;or pharmaceutically acceptable salts thereof.9. Compounds according to any one of the preceding embodiments, whereinA¹ and A² are optionally substituted alkanediyl and are the same ordifferent and are independently selected from optionally substituted

-   -   methylene and    -   ethane-1,2-diyl, or wherein    -   A¹ and R³ together with the nitrogen atom to which they are        bonded form an optionally substituted 4-membered aliphatic        monocyclic ring;        or pharmaceutically acceptable salts thereof.        10. Compounds according to any one of the preceding embodiments        for the use as a medicament.        11. Compounds according to any one of the preceding embodiments        for the use as ferroportin inhibitor.        12. Compounds as defined in any one of the preceding embodiments        for the use in the inhibition of iron transport mediated by        ferroportin or for the use in the prophylaxis and/or treatment        of iron metabolism disorders leading to increased iron levels,        iron overload, diseases related to or caused by increased iron        levels or tissue iron overload-diseases associated with        ineffective erythropoiesis, diseases caused by reduced levels of        hepcidin, or to limit the amount of iron available to pathogenic        microorganisms, such as the bacterium Vibrio vulnificus, and        thereby for the use as adjunctive therapy to treat infections.        13. Compounds as defined in any one of the preceding embodiments        for the use according to embodiment 12 wherein the diseases        related to or caused by increased iron levels or iron overload        comprise thalassemia (beta-thalassemia), haemochromatosis,        neurodegenerative diseases such as Alzheimer's disease and        Parkinson's disease, formation of radicals, reactive oxygen        species (ROS) and oxidative stress, cardiac, liver and endocrine        damage caused by iron overload, and inflammation triggered by        excess iron; and wherein the diseases associated with        ineffective erythropoiesis comprise myelodysplastic syndromes        (MDS, myelodysplasia), polycythemia vera.        14. A medicament containing one or more of the compounds as        defined in any one of the preceding embodiments, the medicament        being preferably for the use as defined in embodiments 12 and        13, and which may further contain one or more pharmaceutical        carriers and/or auxiliaries and/or solvents and/or at least one        further pharmaceutically active compound, in particular a        compound for the prophylaxis and treatment of iron overload,        thalassemia, haemochromatosis, neurodegenerative diseases (such        as Alzheimer's disease or Parkinson's disease) and the        associated symptoms, preferably an iron-chelating compound; and        wherein the medicament is preferably for oral or parenteral        administration.

1: A medicament comprising a compound according to formula (A-II):

wherein R⁴ indicates 1, 2 or 3 optional substituents, which mayindependently be selected from the group consisting of halogen, cyano,optionally substituted alkyl, optionally substituted alkoxy, and acarboxyl group; X¹ is C, N, S or O; X² is C or N; X³ is C, N, S or O;and X⁴ is C, N, or S with the proviso that 1 to 3 heteroatoms X arepresent, and wherein X¹, X³ and X⁴, when having the meaning of C or N,may carry a further substituent; R¹ is selected from the groupconsisting of hydrogen and optionally substituted alkyl; Cycl isselected from the group consisting of substituted aryl and substitutedor unsubstituted heteroaryl; Q is hydrogen or C₁-C₄-alkyl, which mayform a fused 5- or 6-membered ring with Cycl; n is 0 or an integer of 1to 8, preferably n is 0 or 1 to 4, preferably n is 0, 1, 2 or 3; and(a1) A¹ is unsubstituted linear or branched C₁-C₄-alkanediyl; (a2) A² islinear or branched C₁-C₄-alkanediyl, which may be substituted with 1 or2 substituents selected from halogen, hydroxy, an oxo group and an aminogroup or a direct bond; and (a3) R³ is hydrogen, or optionallysubstituted alkyl; or (b1) A¹ and R³ together with the nitrogen atom towhich they are bonded form an optionally substituted 4- to 6-memberedmono- or bicyclic ring; or (b2) R³ and A² together with the nitrogenatom to which they are bonded form an optionally substituted 4- to7-membered ring; or pharmaceutically acceptable salts thereof. 2: Themedicament according to claim 1, wherein Cycl is a substituted orunsubstituted pyridinyl, wherein the compound has the formula (A-IVb):

wherein R⁵ indicates 1 to 4 substituents, independently selected fromthe group consisting of F or Cl, or methyl, trifluoromethyl, orhydroxymethyl, or hydroxy, or methoxy, or an oxo group (═O), forming asubstituted pyridinyl-group of the formula

an amino group selected from the group consisting of —NH₂,monoalkylamino, or dialkylamino, or an aminocarbonyl group, preferablyNH₂—(C═O)—, or cyano, or morpholinyl-group, or Cycl is a substitutedphenyl group, wherein the compound has a formula (A-Vb)

wherein R⁶ indicates 1, 2 or 3 substituents which are independentlyselected from the group consisting of hydroxy, halogen, cyano,optionally substituted alkyl, amino selected from the group consistingof —NH₂, monoalkylamino and dialkylamino, optionally substituted acyl,optionally substituted alkoxy, preferably methoxy, di-fluoromethoxy andtrifluoromethoxy, optionally substituted aryloxy, optionally substitutedheterocyclyloxy, optionally substituted aryl, optionally substitutedheterocyclylyl, and heterocyclyl-substituted sulfonyl of the formula

or pharmaceutically acceptable salts thereof. 3: The medicamentaccording to claim 1, wherein the compound has the formula (A-IVd):

or pharmaceutically acceptable salts thereof. 4: The medicamentaccording to claim 3, wherein R⁵ is selected from the group consistingof Cl or F, and optionally substituted alkyl, or pharmaceuticallyacceptable salts thereof. 5: The medicament according to claim 1,wherein X¹ is N X² is C; X³ is O or S; and X⁴ is N or C, forming a group

respectively wherein * indicates the binding site to theaminocarbonyl-group and ** indicates the binding site to the A¹-group;and wherein X⁴ may carry a further substituent, or wherein X¹ is O or S,X² is C, X³ is N, and X⁴ is C, and wherein Y¹ indicates hydrogen or anoptional substitutent to X⁴; forming a group

respectively, wherein * indicates the binding site to theaminocarbonyl-group and ** indicates the binding site to the A¹-group;or pharmaceutically acceptable salts thereof. 6: The medicamentaccording to claim 1, wherein the further substituents of X¹, X³ and X⁴are independently selected from the group consisting of halogen, andoptionally substituted alkyl, or pharmaceutically acceptable saltsthereof. 7: The medicament according to claim 1, wherein A¹ and A² areoptionally substituted alkanediyl and are the same or different and areindependently selected from optionally substituted methylene andethane-1,2-diyl, or wherein A¹ and R³ together with the nitrogen atom towhich they are bonded form an optionally substituted 4-memberedaliphatic monocyclic ring; or pharmaceutically acceptable salts thereof.8: Medicaments according to claim 1, wherein the compound has astructure selected from the group consisting of Exp. No. Structure 1

2

3

4

5

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12

16

21

35

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279

280

or pharmaceutically acceptable salts thereof. 9: The medicamentaccording to claim 1, wherein the compound has the formula

or pharmaceutically acceptable salts thereof. 10: The medicamentaccording to claim 1, further comprising at least one selected from thegroup consisting of at least one pharmaceutical carrier, at least oneauxiliary and at least one solvent. 11: The medicament according toclaim 1, which is in the form of a formulation for oral or parenteraladministration. 12: A combination formulation comprising the medicamentaccording to claim 1 and at least one additional pharmaceutically activecompound, selected from the group consisting of compounds active in theprophylaxis and treatment of iron overload, thalassemia, orhaemochromatosis, compounds active in the prophylaxis and treatment ofneurodegenerative diseases, Alzheimer's disease, Parkinson's disease,and symptoms associated with the foregoing, and iron-chelatingcompounds. 13: A method for the prophylaxis or treatment of (a) diseasescaused by a lack of hepcidin; or (b) iron metabolism disorders leadingto (i) increased iron levels, (ii) increased iron absorption, or (iii)iron overload; or (c) diseases related to or caused by (i) increasediron levels, (ii) increased iron absorption, or (iii) iron overload; themethod comprising administering, to a patient in need thereof, atherapeutic composition, said therapeutic composition comprising atleast one compound as defined in claim
 1. 14: The method of claim 13,wherein the (a) diseases caused by a lack of hepcidin; or (b) ironmetabolism disorders are selected from the group consisting ofineffective erythropoiesis, myelodysplastic syndromes (MDS,myelodysplasia), polycythemia vera and congenital dyserythropoieticanemia. 15: The method of claim 13, wherein the at least one of (a) ironmetabolism disorders leading to increased iron levels or increased ironabsorption, and (b) iron overload is selected from the group consistingof thalassemia, alpha-thalassemia, beta-thalassemia anddelta-thalassemia, hemoglobinopathy, hemoglobin E disease, hemoglobin Hdisease, haemochromatosis, hemolytic anemia, sickle cell anemia andcongenital dyserythropoietic anemia. 16: A method for the prophylaxisand treatment of infections caused by pathogenic microorganisms in anadjunctive therapy, the method comprising administering, to a patient inneed thereof, a therapeutic composition comprising at least one compoundas defined in claim 1, thereby limiting the amount of iron available tothe pathogenic microorganisms. 17: A method for the prophylaxis and/ortreatment of conditions selected from the group consisting ofneurodegenerative diseases, Alzheimer's disease and Parkinson's disease,comprising, administering to a patient in need thereof, the compound asdefined in claim 1, thereby limiting the deposition or increase of ironin tissue or cells. 18: A method for the prophylaxis and/or treatment ofconditions selected from the group consisting of formation of radicals,reactive oxygen species (ROS) and oxidative stress; cardiac, liver andendocrine damage caused by iron overload; and inflammation triggered byexcess iron, comprising, administering to a patient in need thereof, thecompound as defined in claim
 1. 19: A method for the prophylaxis ortreatment of iron metabolism disorders leading to increased iron levels,increased iron absorption, or iron overload, the method comprising theco-administration of the compound as defined in claim 1 together with atleast one additional pharmaceutically active compound, wherein theco-administration of the combination therapy may be carried out in afixed dose combination therapy by co-administration of the compound asdefined in claim 1 together with at least one additionalpharmaceutically active compound in a fixed-dose formulation; or theco-administration of the combination therapy may be carried out in afree dose combination therapy by co-administration of the compound asdefined in claim 1 together with at least one additionalpharmaceutically active compound in free doses of the respectivecompounds, either by simultaneous administration of the individualcompounds or by sequential use of the individual compounds distributedover a time period; and the at least one additional pharmaceuticallyactive compound of the co-administration of the combination therapy maybe selected from the group consisting of compounds being active inreducing iron overload, Tmprss6-ASO, iron chelators, curcumin,SSP-004184, deferitrin, deferasirox, deferoxamine, deferiprone,antioxidants, n-acetyl cysteine, anti-diabetics, GLP-1 receptoragonists; antibiotics, vancomycin (Van), tobramycin; drugs for thetreatment of malaria; anticancer agents; antifungal drugs; drugs for thetreatment of neurodegenerative diseases, drugs for the treatment ofAlzheimer's disease, drugs for the treatment of Parkinson's disease,drugs comprising dopamine agonists, levodopa, anti-viral drugs,interferon-a, ribavirin, immunosuppressents, cyclosporine A orcyclosporine A derivatives; iron supplements; vitamin supplements; redcell production stimulators; anti-inflammatory biologics;anti-thrombolytics; statins; vasopressors; and inotropic compounds.